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United States 
Environmental Protection 
Agency 


Office of Research and 
Development 
Washington DC 20460 


E P A/600/R-00/068 
October 2000 
www.epa.gov 


Strategy for Research on 
Environmental Risks to 

iVf*> q n 










































EPA/600/R-00/068 
October 2000 


STRATEGY FOR RESEARCH 
ON ENVIRONMENTAL RISKS TO CHILDREN 


U.S. Environmental Protection Agency 
Office of Research and Development 

Washington, DC 


Printed on Recycled Paper 



NOTICE 



This document has been reviewed in accordance with U.S. Environmental Protection 
Agency policy and approved for publication. Mention of trade names or commercial 
products does not constitute endorsement or recommendation for use. 



FOREWORD 


The 1997 Strategic Plan for the Office of Research and Development (ORD) sets forth ORD’s 
vision, mission, and long-term research goals. As part of this strategic process, ORD used the risk 
paradigm to identify EPA’s top research priorities for the next several years. The ORD Strategic Plan 
serves as the foundation for the research strategies and research plans that ORD has developed, or 
is in the process of developing, to identify and describe individual high-priority research topics. One 
of these high-priority topics is to better understand environmental risks to children. 

A team of scientists from ORD and other EPA offices, including the Office of Prevention, 
Pesticides and Toxic Substances; the Office of Water; and the Office of Children’s Health Protection, 
prepared the Strategy for Research on Environmental Risks to Children. The ORD Science Council 
completed an internal review of the strategy in May 1999. Following revisions based on the Science 
Council review, the draft was reviewed by scientists outside EPA. The outcome of these reviews is a 
strategy that establishes EPA’s long-term program goals and objectives for research in children’s risk 
and documents the rationale for the chosen program direction. 

The key scientific questions this strategy sets out to address are: 

■ What are the adverse effects from children’s exposures to environmental agents that are 
qualitatively or quantitatively different from effects in similarly exposed adults? What are the 
near-term and delayed effects of childhood exposures? What are the characteristics of the 
environmental agents associated with these effects? 

■ What are the specific periods of development when exposure to environmental substances 
can cause adverse health effects? 

■ What are the best in vitro models and in vivo animal models for screening for and identifying 
hazards to children? 

■ To what environmental substances are children more highly exposed? How do exposures 
differ with age? What factors contribute to higher exposures? 

■ What are the relationships between exposures to children and adverse health effects 
observed in childhood or later? What factors in the child’s environment can increase risks? 

■ How can laboratory and human data be used to predict responses to childhood exposures? 

■ What is the variation in exposure and susceptibility within members of the same age group, 
and what are the factors that contribute to this variation? 

■ What adverse effects from children's exposures to mixtures are quantitatively or qualitatively 
different from effects in similarly exposed adults? 

■ What are the uncertainties in estimating environmental risks to children and how can they be 
characterized in risk assessment? What are the most effective methods for communicating 
results, data, and risks to risk assessors, risk managers, and the public? 

■ What are the specific environmental agents and pathways of exposure where risk 
management research will be effective in addressing known risks to children? What are the 
most effective methods for reducing environmental risks to children? 


iii 



To answer these questions, this strategy groups its research priorities into the following five 
areas: (1) development of data for risk assessment, (2) development of risk assessment methods and 
models, (3) experimental methods development, (4) risk management and risk communication, and 
(5) cross-cutting issues including variation in susceptibility and cumulative risk. 

This research strategy is an important planning tool because it makes clear the rationale for, 
and the intended products of, EPA’s research on children’s environmental health and helps EPA 
effectively communicate its program to clients, stakeholders, and the public. This research strategy 
is also an important accountability tool, enabling EPA to clearly track progress toward achieving its 
research goals as required by the 1993 Government Performance and Results Act. 


E. Timothy Oppelt 

Acting Deputy Assistant Administrator 
for Science, ORD 


IV 



EPA AUTHORS, CONTRIBUTORS, AND REVIEWERS 


Executive Lead 

William H. Farland, Director, National Center for Environmental Assessment (NCEA), Office of Research 
and Development (ORD), U.S. Environmental Protection Agency 

The strategy was developed by a science team with representatives from ORD’s laboratories and centers 
and from the Office of Prevention, Pesticides, and Toxic Substances (OPPTS); the Office of Water; and the Office of 
Children’s Health Protection (OCHP). The following are the members of the science team: 

Authors 

John Cicmanec, ORD/National Risk Management Research Laboratory (NRMRL) 

Karen Hammerstrom (Chair), ORD/NCEA 

Stephen Hern, ORD/National Exposure Research Laboratory (NERL) 

Gary Kimmel, ORD/NCEA 
William Nelson, ORD/NERL 

Ralph Smialowicz, ORD/National Health and Environmental Effects Research Laboratory (NHEERL) 

Contributing Science Team Members 

Andrew Avel, ORD/NRMRL 

Karl Baetcke, OPPTS/Office of Pesticide Programs (OPP) 

David Chen, OCHP 

Amal Mahfouz, Office of Water 

Suzanne McMaster, ORD/NHEERL 

Chris Saint, ORD/National Center for Environmental Research (NCER) 

Jennifer Seed, OPPTS/Office of Pollution Prevention and Toxics (OPPT) 

Wiliam Steen, ORD/NERL 
Karen Whitby, OPPTS/OPP 

The following ORD managers and scientists contributed to the development of this strategy through their 
careful review and insightful comments on the ORD Science Council (Internal) Review Draft: 

ORD Science Council Members 

Harold Zenick, Lead Reviewer, ORD/NHEERL 
Judith Graham, ORD/NERL 
Robert Kavlock, ORD/NHEERL 
Hugh McKinnon, ORD/NRMRL 
Vanessa Vu, ORD/NCEA 

Other ORD Reviewers 

Larry Claxton, ORD/NHEERL 
Elaine Francis, ORD/NCER 
Hillel Koren, ORD/NHEERL 
Martha Moore, ORD/NHEERL 
Jennifer Orme-Zavaleta, ORD/NHEERL 
Hugh Tilson, ORD/NHEERL 


v 









PEER REVIEW AND COMMENTS 


An external peer review of the Strategy for Research on Environmental Risks to Children was organized by the 
Eastern Research Group (ERG). A peer review workshop was held on November 9 and 10, 1999, in Washington, DC. 

Peer Review Chair 

John De Sesso, Ph.D., Director, Biomedical Research Institute, Mitretek Systems, McLean, VA 
Peer Review Members 

Edward Avol, M.S., Associate Professor, Department of Preventive Medicine, University of Southern California 
School of Medicine, Los Angeles, CA 

Cynthia Bearer, M.D., Ph.D., Assistant Professor, Department of Pediatrics and Department of Neurosciences, 
Division of Neonatology, Case Western Reserve University, Cleveland, OH 

Joan Cranmer, Ph.D., ATS, Professor of Pediatrics and Toxicology, Department of Pediatrics, University of 
Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR 

George Daston, Ph.D., Research Fellow, Miami Valley Laboratories, Procter & Gamble, Ross, OH 

Warren Foster, Ph.D., Associate Director/Director of Research, Center for Women's Health, Cedars-Sinai 
Medical Center, Beverly Hills, CA 

Howard Morrison, Ph.D., Chief, Behavioural Risk Assessment, Cancer Bureau, Health Canada, Ottawa, Ontario 

Rossanne Philen, M.D., M.S., Acting Associate Director for Science, Health Studies Branch, National Center 
for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 

William Slikker, Ph.D., Director, Division of Neurotoxicology, National Center for Toxicology Research, Food 
and Drug Administration, Jefferson, AR 

Other External Review and Comment 

EPA Children’s Health Protection Advisory Committee (Reigart, J.R. 2000. Letter to Carol M. Browner, 
Administrator, U.S. EPA, dated January 21,2000, from J. Routt Reigart, M.D., Chair, Children's Health 
Protection Advisory Committee) 

Andy Breslin, Physicians Committee for Responsible Medicine (Observer comment at Nov. 9-10, 1999, Peer 
Review Workshop) 

Keith Harrison, Michigan Environmental Science Board (Observer comment at Nov. 9-10, 1999, Peer Review 
Workshop) 


ACKNOWLEDGMENTS 


The external peer review was administered by ORD's Office of Science Policy (OSP) through a contract with 
the Eastern Research Group (ERG). The authors would like to thank the ERG Work Assignment Manager, Edward 
Washburn, OSP, who was the EPA lead in organizing the peer review. The authors would also like to thank OSP 
Director Dorothy Patton, Donna Witherspoon and Elaine Francis of OSP, and J. Deanna Easley (Office of 
Administration and Resource Management) for their help in the administration of the peer review. Kate Schalk of 
ERG managed the peer review, assisted by Jan Connery, Naida Gavrelis, Melanie Russo, Laurie Stamatatos, and 
Meg Vrablik, all of ERG. 

The cover of the strategy was designed by Stephen E. Wilson (ORD/NRMRL). 


VI 






TABLE OF CONTENTS 


ACRONYMS. ix 

GLOSSARY .x 

EXECUTIVE SUMMARY . EX-1 

1. INTRODUCTION. 1 

1.1. Scope and Definitions. 1 

1.2. Rationale for the Children’s Health Program. 1 

1.3. Research Questions. 3 

1.4. Goals and Objectives . 3 

1.5. ORD Research Strategies and Plans. 3 

1.6. Organization . 3 

2. APPROACHES TO RISK ASSESSMENT. 5 

2.1. The Standard Regulatory Approach. 5 

2.2. Future Directions in EPA Risk Assessment . 6 

3. IMPLEMENTATION OF LEGISLATION AND POLICY ON CHILDREN’S ENVIRONMENTAL HEALTH. 8 

4. RESEARCH DIRECTIONS . 10 

4.1. Research Needs and Recommendations. 10 

4.2. Current Research . 10 

4.2.1. National Testing Programs. 10 

4.2.2. Modes of Action and Modeling of Physiological/Biological Processes. 10 

4.2.3. Studies in Human Populations. 13 

4.2.4. Exposure-Dose-Response Modeling and Risk Assessment . 14 

4.2.5. Risk Management and Risk Communication . 15 

4.3. Research Areas and Priorities . 16 

4.3.1. Laboratory Studies and Surveys. 17 

4.3.1.1. Biology of Toxicant-Induced Tissue and Organ Damage 

in the Developing Organism . 17 

4.3.1.2. Relationship between Exposure to Environmental Agents 

and Adverse Health Effects in Human Populations . 18 

4 3.1.3. Multimedia, Multipathway Exposures in Human Populations. 20 

4.3.1.4. Analysis of Factors Contributing to Exposure. 21 

4.3.2. Risk Assessment Methods and Models. 22 

4.3.2.1. Methods and Models for Using Biological Data in Risk Assessment. 22 

4.3.2.2. Exposure Modeling and Use of Exposure Data in Risk Assessment. 23 

4.3.3. Methods for Studying Effects and Exposure in Humans and Animal Models. 23 

4.3.3.1. In Vivo/In Vitro Methods for Hazard Identification. 23 

4.3.3.2. Methods for Measuring Exposures and Effects in Infants and Children 

and to Aid in Extrapolations between Animals and Humans . 24 

4.3.4. Risk Management Research and Risk Communication. 25 

4.3.4.1. Multimedia Control Technologies that Account for the Susceptibilities 

of Children . 25 

4.3.4.2. Methods for Reducing Exposure Buildup of Contaminants 

in Indoor Environments. 26 

4.3.4.3. Communication of Risks and Development of Risk Reduction Techniques 

Through Community Participation . 26 

4.3.5. Cross-Cutting Issues . 27 

4.3.5.1. Variation in Susceptibility and Exposure in Children . 27 

4.3.5.2. Cumulative Risks to Children. 28 

4.4. Linking and Summary of Research Areas. 28 

5. GUIDANCE FOR IMPLEMENTATION. 34 

6. REFERENCES. 36 

APPENDIX A. GROWTH AND DEVELOPMENT FROM BIRTH THROUGH ADOLESCENCE .A-1 

vii 
















































TABLE OF CONTENTS (continued) 


APPENDIX B. ORD RESEARCH PLANS AND STRATEGIES.B-1 

APPENDIX C. RESEARCH RECOMMENDATIONS . C-1 

APPENDIX D. FEDERAL RESEARCH IN CHILDREN’S ENVIRONMENTAL HEALTH . D-1 

APPENDIX E. CROSS TABULATION OF RESEARCH QUESTIONS AND RESEARCH AREAS .E-1 

APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS.F-1 

LIST OF FIGURES 

Figure 1. Objectives of the ORD Strategy for Research on Environmental Risks to Children. 4 

Figure 2. Pesticides in Young Children: A NERL/NHEERL Collaboration. 34 

Figure 3. Pesticides and Children in Minnesota: A NHEXAS Study and a STAR Grant . 34 

Figure 4. Guiding Principles for Implementation . 35 

LIST OF TABLES 

Table 1. Research Recommendations and Needs. 11 

Table 2. Summary of Research Areas . 29 


viii 














ACRONYMS 


AHS 
ATS DR 

BBDR 

CDC 

CHEHSIR 

DART 

DNA 

EPA 

FDA 

FIFRA 

FQPA 

GPRA 

HUD 

IEUBK 

IRIS 

ITC 

NAAQS 

NAS 

NCEA 

NCER 

NCEH 

NCHS 

NCI 

NERL 

NHANES 

NHEERL 


Agricultural Health Study 
Agency for Toxic Substance and Disease 
Registry 

Biologically based dose response modeling 
Centers for Disease Control and Prevention 
Children’s Environmental Health and Safety 
Inventory of Research 

Developmental and Reproductive Toxicology 
Database 

Deoxyribonucleic Acid 
U.S. Environmental Protection Agency 
U S. Food and Drug Administration 
Federal Insecticide, Fungicide, and 
Rodenticide Act 
Food Quality Protection Act 
Government Performance and Results Act 
U.S. Department of Housing and Urban 
Development 

Integrated Exposure, Uptake, Biokinetic Model 
Integrated Risk Information System 
Interagency Testing Committee 
National Ambient Air Quality Standards 
National Academy of Sciences 
National Center for Environmental Assessment 
(EPA/ORD) 

National Center for Environmental Research 
(EPA/ORD) 

National Center for Environmental Health 
(CDC) 

National Center for Health Statistics (CDC) 
National Cancer Institute 
National Exposure Research Laboratory 
(EPA/ORD) 

National Health and Nutrition Examination 
Survey 

National Health and Environmental Effects 
Research Laboratory (EPA/ORD) 


NHEXAS 

NHLBI 

NIAID 

NIDCR 

NICHD 

NIEHS 

NIH 

NIOSH 

NOAEL 

NOEL 

NRMRL 

NTP 

OCHP 

OPP 

OPPTS 

ORD 

OSWER 

PBPK 

PCB 

PM 

PM10 

RFA 

RfC 

RfD 

SDWA 

STAR 

TSCA 


National Human Exposure Assessment Survey 
National Heart, Lung, and Blood Institute 
National Institute of Allergy and Infectious 
Diseases 

National Institute of Dental and Craniofacial 
Research 

National Institute for Child Health and Human 
Development 

National Institute of Environmental Health 
Sciences 

National Institutes of Health 
National Institute for Occupational Safety and 
Health 

No observed adverse effect level 
No observed effect level 
National Risk Management Research Laboratory 
(EPA/ORD) 

National Toxicology Program 
Office of Children’s Health Protection (EPA) 
Office of Pesticide Programs (EPA/OPPTS) 
Office of Prevention, Pesticides, and Toxic 
Substances (EPA) 

Office of Research and Development (EPA) 
Office of Solid Waste and Emergency Response 
(EPA) 

Physiologically based pharmacokinetic modeling 
Polychlorinated biphenyl 
Particulate matter 

Particulate matter less than 10 pm in diameter 
Request for applications 
Reference concentration 
Reference dose 
Safe Drinking Water Act 
EPA/ORD Science To Achieve Results 
extramural grants program 
Toxic Substances Control Act 


IX 



GLOSSARY 


Aggregate exposure: The combined exposure of an 
individual or defined population to a specific agent or stressor 
via all relevant routes, pathways, and sources. 

Aggregate risk: The risk resulting from aggregate exposure to 
a single agent or stressor. 

Biological markers (biomarkers): Indicators signaling events 
in biological systems or samples. There are three classes of 
biomarkers-exposure, effect, and susceptibility. A marker of 
exposure is an exogenous substance or its metabolite(s) or 
the product of an interaction between a xenobiotic agent and 
some target molecule or cell that is measured in a 
compartment within an organism. A marker of effect is a 
measurable biochemical, physiological, or other alteration 
within an organism that, depending on magnitude, can be 
recognized as an established or potential health impairment or 
disease. A marker of susceptibility is an indicator of an 
inherent or acquired limitation of an organism’s ability to 
respond to the challenge of exposure to a specific xenobiotic 
(NRC 2000). 

Biologically based dose response (BBDR) model: A model 
that describes biological processes at the cellular and 
molecular level linking the target organ dose to the adverse 
effect. 

Cumulative risk: The combined risk from aggregate 
exposures to multiple agents or stressors. 

Developmental toxicology: The study of adverse effects on 
the developing organism that might result from exposure (of 
either parent) prior to conception, during prenatal development, 
or from postnatal development to the time of sexual maturation. 

Deoxyribonucleic Acid (DNA): A complex macromolecule 
that is composed of nucleic acids (adenine, guanine, cytosine, 
and thymine) and is found in cellular organisms. DNA carries 
all the genetic information necessary to determine the specific 
properties of an organism. 

Dose: The amount of a substance available for interactions 
with metabolic processes or biologically significant receptors 
after crossing the outer boundary of an organism. The 
potential dose is the amount ingested, inhaled, or applied to 
the skin. The applied dose is the amount presented to an 
absorption barrier and available for absorption (although not 
necessarily having yet crossed the outer boundary of the 
organism). The absorbed dose is the amount crossing a 
specific absorption barrier (e.g., the exchange boundaries of 
the skin, lung, and digestive tract) through uptake processes. 
Internal dose is a more general term denoting the amount 
absorbed without respect to specific absorption barriers or 
exchange boundaries. The amount of the chemical available 
for interaction by any particular organ or cell is termed the 
delivered or biologically effective dose for that organ or cell. 

Dose-response assessment: The determination of the 
relationship between the magnitude of administered, applied, 
or internal dose and a specified biological response. 


Exposure: Contact of a chemical, physical, or biological agent 
with the outer boundary of an organism. Exposure is quantified 
as the concentration of the agent in the medium over time. 

Exposure assessment: The determination or estimation of the 
magnitude, frequency, duration, and route of exposure. 

Exposure pathway: The physical course an environmental 
agent takes from the source to the individual exposed. 

Exposure route: The way an environmental agent enters an 
organism (e g., by ingestion, inhalation, or dermal absorption). 

Hazard identification: A description of the potential adverse 
health effects attributable to a specific environmental agent and 
the mechanisms by which agents exert their toxic effects. 

Lowest observed adverse effect level (LOAEL): The lowest 
exposure at which there is a statistically or biologically 
significant increase in the frequency of an adverse effect when 
compared with a control group. 

Mechanism of action: The complete sequence of biological 
events that must occur to produce the toxic effect. 

Mode of action (MOA): A less-detailed description of the 
mechanism of action in which some but not all of the sequence 
of biological events leading to a toxic effect is known. 

No observed adverse effect level (NOAEL): The highest 
exposure at which there is no statistically or biologically 
significant increase in the frequency of an adverse effect when 
compared with a control group. 

No observed effect level (NOEL): The highest exposure at 
which there is no statistically or biologically significant increase 
in the frequency of any effect, adverse or not, compared with 
a control group. 

Nonthreshold effect: An effect for which it is assumed that 
there is no dose, no matter how low, for which the probability 
of an individual’s responding is zero. 

Pharmacodynamics: The determination and quantitation of 
the sequence of events at the cellular and molecular levels 
leading to a toxic response to an environmental agent (also 
called Toxicodynamics). 

Pharmacokinetics: The determination and quantitation of the 
time course of absorption, distribution, biotransformation, and 
excretion of chemicals (also called toxicokinetics). 

Physiologically based pharmacokinetic (PBPK) model: A 

model that estimates the dose to a target tissue or organ by 
taking into account the rate of absorption into the body, 
distribution among target organs and tissues, metabolism, and 
excretion. 

Program Office: An EPA organizational unit that administers 
a major EPA program (Air and Radiation; Water; Prevention, 
Pesticides, and Toxic Substances; and Solid Waste and 


x 



Emergency Response) 

Reference concentration (RfC): An estimate of a continuous 
inhalation exposure to the human population (including 
sensitive subgroups) that is likely to be without an appreciable 
risk of deleterious noncancer effects during a lifetime. 

Reference dose (RfD): An estimate of a daily dose to the 
human population (including sensitive subgroups) that is likely 
to be without an appreciable risk of deleterious noncancer 
effects during a lifetime. 

Risk: The probability of adverse effects resulting from 
exposure to an environmental agent. 

Risk characterization: The integration of information on 
hazard, exposure, and dose-response to provide an estimate 
of the likelihood that any of the identified adverse effects will 
occur in exposed people. 

Risk assessment: The evaluation of scientific information on 


the hazardous properties of environmental agents and on the 
extent of human exposure to those agents. The product of the 
risk assessment is a statement regarding the probability that 
populations or individuals so exposed will be harmed and to 
what degree. 

Susceptibility: Increased likelihood of an adverse effect 
related to an individual’s developmental stage. 

Threshold effect: An effect for which there is some dose 
below which the probability of an individual’s responding is 
zero. 

Uncertainty Factor: One of several factors used to calculate 
an exposure level that will not cause toxicity from experimental 
data. Uncertainty factors are used to account for the variation 
in susceptibility among humans, the uncertainty in extrapolating 
from experimental animal data to humans, the uncertainty in 
extrapolating from data from studies in which agents are given 
for less than a lifetime, and other uncertainties such as using 
LOAEL data instead of NOAEL data. 


xi 






























































































OFFICE OF RESEARCH AND DEVELOPMENT 

STRATEGY FOR RESEARCH 
ON ENVIRONMENTAL RISKS TO CHILDREN 


EXECUTIVE SUMMARY 


The U.S. Environmental Protection Agency (EPA) is 
committed to promoting a safe and healthy environment for 
children by ensuring that all EPA regulations, standards, 
policies, and risk assessments consider special childhood 
vulnerabilities to environmental pollutants. 

Windows of vulnerability exist during development, 
particularly during early gestation, but also throughout 
pregnancy, infancy, childhood, and adolescence, when 
toxicants may permanently alter the function of a system. 
Children may also be more vulnerable than adults because of 
differences in absorption, metabolism, storage, and excretion, 
resulting in higher biologically effective doses to target tissues. 
Children can be more highly exposed than adults because of 
proportionately higherfood intake and breathing rates, different 
diets, and activities such as playing on floors that result in 


greater contact with environmental contaminants. 

These health threats to children are often difficult to 
recognize and assess because of limited understanding of 
when and why children’s exposures and responses are 
different from those of adults. Research is needed to address 
these issues and find opportunities and approaches for risk 
reduction. This document provides the strategic direction for 
EPA’s research program in children’s health, conducted by the 
Office of Research and Development (ORD). 

The primary objective of the ORD Children’s Health 
program is to conduct the research and provide the methods to 
reduce uncertainties in EPA risk assessments for children, 
leading to effective measures for risk reduction. 


— 

Objectives of the Strategy for 
Research on Environmental Risks to Children 

■ Establish direction for a long-term, stable core research program in children’s environmental health that leads to 
sustained risk reduction through more accurate, scientifically based risk assessments for children. 

■ Identify research to answer the key questions about children’s environmental health risks and increase our 
understanding of when children respond differently from adults to toxic agents and why. 

■ Identify research that will help to reduce children’s risks. 

■ Provide a research agenda that identifies research priorities for the ORD intramural and extramural research 
programs. 

■ Inform EPA scientists, risk assessors, and risk managers of the research related to children at EPA and other Federal 
agencies. 

■ Provide guiding principles for implementation. 


EX-1 




Research Questions 


Children’s risk is a topic as broad and varied as 
human health risk assessment. Groups of experts have 
identified dozens if not hundreds of research issues and needs, 
addressing various age groups, subpopulations, disease 


endpoints, biomarkers of disease, mechanisms of action, 
exposure pathways, environmental contaminants, and 
physiological and biological characteristics affecting doses. 




Children’s Risk Topics 



Health Endpoints 


■ 

Cancer 


■ 

Neurotoxicity 


■ 

Immune system effects 


■ 

Asthma and other respiratory effects 


■ 

Reproductive effects 


■ 

Other birth defects (e g., death, malformation, growth alteration) 



Environmental Health Threats 


m 

Outdoor and indoor air pollution 


m 

Pesticides 


m 

Environmental tobacco smoke 


■ 

Microbes and other drinking water contaminants 


■ 

Endocrine disruptors 


■ 

Specific compounds such as lead, mercury, PCBs, vinyl chloride 


■ 

Mixtures of pollutants 


A strategy for research in children’s environmental 
health must be broad enough to address diverse environmental 
contaminants, endpoints, and special groups such as children 


living on farms and urban children. Priorities may shift rapidly 
as more becomes known about the impact of environmental 
agents on children’s health. 


— 

Research Questions 

■ What are the effects from children’s exposures to environmental agents that are different from effects in adults? 

■ What are the periods of development when exposure to environmental substances can cause adverse health effects? 

■ What are the best in vitro models and in vivo animal models for screening for and identifying hazards to children? 

■ To what environmental substances are children more highly exposed? What factors contribute to higher exposures? 

■ What are the relationships between exposures to children and adverse health effects observed in childhood or later? 

■ How can laboratory and human data be used to predict responses to childhood exposures? 

■ What is the variation in exposure and susceptibility within members of the same age group? 

■ What are the adverse effects from children’s exposures to mixtures? 

■ What are the uncertainties in estimating environmental risks to children? 

■ What are the most effective methods for communicating and reducing environmental risks to children? 


EX-2 










Research 

The strategy was developed by a science team 
composed of members from ORD; the Office of Prevention, 
Pesticides, and Toxic Substances (OPPTS); the Office of 
Water; and the Office of Children’s Health Protection (OCHP). 
The strategy is organized into 5 main topics encompassing 13 
research areas. The science team ranked each research area 
as high, medium, or low. The areas ranked high were those 
judged to have the greatest potential to improve EPA risk 


Approach 

assessments or to address directly the reduction of risks 
specific to children. Feasibility based on the current state of 
scientific knowledge, ORD’s capacity and capability to perform 
the research, opportunities to build upon the research 
conducted in other agencies, development and maintenance of 
needed expertise within ORD, and the balance between short- 
and long-term research were also considered in the rankings. 


— 

Research Priorities 

■ Development of data to reduce uncertainties in risk assessment 

Mode-of-action research (High) 

Epidemiology and clinical studies (High) 

- Exposure field studies (High) 

Activity pattern and exposure factor studies (High) 

■ Development of risk assessment methods and models 

Methods and models for assessing dose-response relationships in children (High) 

Methods and models for using exposure data in risk assessments for children (High) 

■ Experimental methods development 

Methods for hazard identification and studying mode of action (High) 

- Methods for measuring exposure and effects in children and to aid in extrapolations between animals and 
children (Medium) 

■ Risk management and risk communication 

Multimedia control technologies (Low) 

Reduction of exposure buildup of contaminants indoors (High) 

Communication of risk (High) 

■ Cross-cutting research 


Variation in human susceptibility (Medium) 
Cumulative risk (Medium) 



EX-3 






Implementation 


Implementation of the strategy will be accomplished 
through detailed research plans developed by ORD’s 
laboratories and centers. To assist in the development of 
these plans, the strategy provides long-term outcomes and 
short-term results for each of the highly ranked research areas 
and guiding principles for implementation. 

Mode-of-Action and Dose-Response Assessment 
(§§4.3.1.1, 4.3.2.1,4.3.3.1) 

Long-Term Outcomes 

■ Mechanism-of-action experimentation facilitates the 
extrapolation of animal and experimental model data 
to humans, enhancing ability to predict and study 
adverse effects in humans. Mode of action becomes 
an integral component of risk assessment. Advances 
in genomics/proteomics are incorporated into EPA’s 
risk assessment methodologies. 

■ Broadly applicable physiologically based 
pharmacokinetic (PBPK) models and biologically 
based dose-response (BBDR) models are routinely 
used to produce more accurate risk assessments for 
children, making full use of pharmacokinetic and 
mode-of-action data. 

Short-Term Outputs 

■ Develop better quantitative characterizations of dose 
to target tissue in developing organisms to replace 
default assumptions in children’s risk assessments. 

■ Link developmental effects at the tissue, organ, and 
system levels with the underlying effects at the 
cellular and molecular levels. Develop first- 
generation biologically based predictive models. 

■ Develop and validate sensitive and predictive 
methods using laboratory animals to determine mode 
of action by linking developmental effects at the 
tissue, organ, and system levels with the underlying 
effects at the cellular and molecular levels. 

■ Validate in vitro assays (using either animal or human 
biological material) for inclusion in the overall risk 
assessment process. 

■ Validate and apply currently available test methods 
and emerging methods in genomics/proteomics and 
molecular biological approaches, useful for 
understanding and elucidating mode of action, in 
developmental toxicity testing. 


■ Evaluate the appropriateness of the assumptions in 
current EPA risk assessment approaches and how 
they may be supported or modified by biological data. 

■ Develop and refine PBPK models applied to the 
developing animal, with the intent of eventual 
extrapolation to embryos, fetuses, infants, and 
children. 

■ Develop and refine BBDR models applied to the 
developing animal with the intent of extrapolation to 
embryos, fetuses, infants and children. 

■ Identify biological pathways, environmental factors, 
and their interactions that are important to 
understanding normal and abnormal development, 
with a focus on incorporation of such information into 
predictive models of developmental toxicology and 
not solely on the generation of basic information on 
child development. 

■ Define how experimental animal models mirror child 
development and develop appropriate correction 
factors for species differences. 

■ Incorporate information from dose-response, 
pharmacokinetic, and mode-of-action studies in 
animals into models that more accurately predict 
children’s risks. 

■ Develop first-generation methods, guidance, and data 
for broad application of modes of action and 
pharmacokinetics in EPA risk assessments for 
children 

Exposure and Epidemiologic Research (§§4.3.1.2, 4.3.1.3, 

4.3.1.4, 4.3.2.2) 

Long-Term Outcomes 

■ Environmental agents and other factors contributing 
to adverse effects in children are identified, status and 
trends in children’s health and exposure to 
environmental agents are characterized, and risk 
reduction methods are successfully implemented. 

■ Status and trends in children’s exposures to 
environmental agents are characterized using 
baseline data developed in this program. Highly 
exposed subpopulations of children are identified, 
important sources and pathways of children’s 
exposures are delineated, and risk management 
interventions are successfully implemented. 


EX-4 



■ Residential exposure factors for children are 
characterized by age and sex for the national 
population, regional populations, highly exposed 
groups, and susceptible groups. Factors include 
activity patterns (time spent in a given activity and 
frequency of occurrence), soil and dust ingestion 
rates, factors reflecting transfer of environmental 
agents from objects and surfaces children commonly 
touch, and factors related to ingestion of chemical 
residues on surfaces. 

■ A broadly applicable probabilistic total-exposure 
model capable of linking to a PBPK model is available 
to estimate children’s exposure to pesticides, 
producing more accurate assessments of children’s 
exposure and reducing use of default values and 
safety factors in the assessment when sufficient input 
data are available. 

Short-Term Outputs 

■ Analyze relationships between childhood exposures 
to air pollutants and respiratory effects under the 
ORD Science To Achieve Results (STAR) extramural 
grants program. 

■ Analyze relationships between childhood exposures 
to pesticides and neurological effects under the STAR 
program. 

■ Develop, refine, and pilot methods for conducting a 
hypothesis-based longitudinal study of developmental 
disorders in a large birth cohort under the U S. Task 
Force on Children’s Environmental Health and Safety. 

■ Conduct analysis of existing data from the National 
Human Exposure Assessment Survey (NHEXAS), the 
National Health and Nutrition Examination Survey 
(NHANES), and the STAR grants to provide answers 
to the extent possible on whether children are more 
highly exposed, which age groups are more highly 
exposed, and important sources and pathways. 

■ Develop new sampling protocols, questionnaires, and 
study designs based on previous studies of children’s 
exposure. 

■ Design and initiate field studies to answer questions 
about children’s exposure, with Federal partners 
where feasible. 

■ Identify high-priority exposure variables for study 
through preliminary exposure analysis. 


■ Design and complete activity pattern survey 
addressing high-priority issues for children. 

■ Complete two studies on other high-priority exposure 
variables for children. 

■ Assess children’s total pesticide exposure and refine 
existing exposure models based on data from 
NHEXAS, NHANES, and the STAR program. 

■ Analyze models in EPA’s Office of Pesticide 
Programs (OPP) Standard Operating Procedures for 
estimating exposure of children to pesticides, identify 
important pathways of exposure, and provide 
assessment support. 

Risk Management and Risk Communication (§§4.3.4.2, 

4.3.4.3) 

Long-Term Outcomes 

■ Broadly applicable methods for removing chemicals 
from residential environments and for preventing 
exposure in the residential environment (e.g., through 
encapsulation) are used by the Superfund program, 
EPA Regional Offices, State and local public health 
and environmental agencies, and others to achieve 
cost-effective cleanup to safe levels for children. 

■ Through implementation of better methods of 
communicating scientific information about risk and 
working with communities to reduce risk, EPA 
strengthens its community-based risk assessment 
and risk management programs. 

Short-Term Outputs 

■ Develop a method to remove pesticides and other 
chemicals from building structures and carpets or to 
prevent exposure (e.g., through encapsulation), using 
methyl parathion as a prototype. 

■ Implement risk intervention programs in several 
communities and publish journal articles on 
effectiveness of risk intervention approaches (output 
of STAR program’s Centers for Children’s 
Environmental Health and Disease Prevention). 

■ Compare methods for communicating risks of 
pesticides on foods (output of current STAR program 
grant). 


EX-5 



Guiding Principles for Implementation 

When designing a research study, investigators should consider the impact of the results on EPA risk assessments 
for children. Requests for Applications (RFAs) in ORD intramural and STAR programs should ask investigators to 
specify the potential impact of results on the EPA risk assessment process. 

A multidisciplinary research program that is coordinated across the ORD laboratories and centers is encouraged. 
RFAs for cross-laboratory/center intramural projects and fostering of contact between extramural grantees and ORD 
scientists are encouraged. 

Outreach, coordination, and partnership with other Federal agencies is essential, particularly in the areas of human 
studies and biological mechanisms of action. 

Toxicologists, epidemiologists, clinicians, and exposure scientists are encouraged to work collaboratively during all 
phases of research planning, development, and implementation. 

ORD needs to develop and maintain intramural expertise to be able to incorporate new data and methods into EPA 
risk assessments. Use of biological data in risk assessment is a high priority. A stable intramural research program 
with adequate support is essential to achieving this capability. 

Research across more than one endpoint is encouraged where possible, such as research on mechanisms that can 
lead to multiple endpoints and endpoints affecting the same target organ. 


Risk reduction research and risk management goals should be considered throughout the course of this program. 







OFFICE OF RESEARCH AND DEVELOPMENT 
STRATEGY FOR RESEARCH 
ON ENVIRONMENTAL RISKS TO CHILDREN 

1. INTRODUCTION 


The U.S. Environmental Protection Agency (EPA) is 
committed to promoting a safe and healthy environment for 
children through regulations, standards, policies, and risk 
assessments that consider special childhood vulnerabilities to 
environmental agents (EPA 1996a). Many environmental 
health threats to children may not be recognized because we 
do not have a complete understanding of when and why 
children’s exposures and responses differfrom those of adults. 
This may affect EPA’s ability to identify environmental hazards, 
assess risks, and act to protect children. 

EPA’s Office of Research and Development (ORD) is 
responsible for conducting research to provide the scientific 
foundation for risk assessment and risk management at EPA. 
In 1998, ORD initiated the Children’s Health program to 
support research on environmental risks to children. ORD and 
the Office of Prevention, Pesticides, and Toxic Substances 
(OPPTS) charged a team of ORD and OPPTS scientists with 
developing the Strategy for Research on Environmental Risks 
to Children (EPA 1997a) 1 to provide strategic direction for the 
Children’s Health program. 

1.1. Scope and Definitions 

This strategy addresses adverse effects on the 
developing organism that may result from exposure to 
environmental agents, starting with preconception exposures 
to parents and continuing through gestation and postnatally up 
to the time of maturation of all organ systems. 2 Because organ 
systems reach maturity at different times, developmental 
phases of interest will vary by organ system. Variation in 
exposure resulting from age-related differences in activity 


Representatives of the EPA Office of Water and the 
EPA Office of Children’s Health Protection (OCHP) were 
added to the team at the request of those offices. 

2 In the Guidelines for Developmental Toxicology Risk 
Assessment (EPA 1991), EPA defined developmental 
toxicology, in part, as follows: “The study of adverse effects on 
the developing organism that may result from exposure prior to 
conception (either parent), during prenatal development, or 
post natally to the time of sexual maturation. Adverse 
developmental effects may be detected at any point in the life 
span of the organism....” 


patterns, diet, and physiological characteristics will also help 
define developmental phases of interest. The scope includes 
effects that are not observed until adulthood. For convenience, 
the terms "childhood,” “child,” and “children” are used to refer 
to all the individuals within the scope of the strategy. 

The Children’s Health program began as part of an 
Administrator’s Initiative aimed at ensuring that risks to children 
are considered in all EPA actions. An expanded program of 
research in children’s issues is part of the Initiative. 
Historically, ORD has conducted research in male and female 
reproductive toxicity, embryo and fetal toxicity, and postnatal 
functional deficits. ORD research supporting the Air, Water, 
Waste, and Pesticides and Toxics programs deals with media- 
specific issues, such as the impact of air pollution on childhood 
asthma and the effects of lead on small children. This strategy 
builds upon the ongoing research program. 

1.2. Rationale for the Children’s 
Health Program 

There is evidence of age-related differences in 
exposure and susceptibility to some environmental agents that 
warrants further investigation (ILSI 1992, ILSI 1996, NRC 
1993, WHO 1986). Depending on the agent, age-related 
differences may increase, decrease, or have little impact on the 
risk to children. 

As a rationale for the Children’s Health program, this 
section provides a brief description of some of the documented 
vulnerabilities of children. A more detailed description of 
potential postnatal vulnerabilities is contained in Appendix A. 

There are specific periods or windows of vulnerability 
during development, particularly during early gestation but also 
throughout pregnancy and early childhood through 
adolescence, when toxicants might permanently alter the 
function of a system (Rodier 1980, Bellinger et al. 1987). At 
birth, most organs and systems of the body have not achieved 
structural or functional maturity. Physical growth and functional 
maturation continue through adolescence, with the rates 
varying among the different tissues, organs, and systems of the 
body. Organs and systems that continue to undergo 
maturation during infancy and childhood include the lungs, 
kidneys, and liver, and the immune, nervous, endocrine, 
reproductive, and gastrointestinal systems (Hoar and Monie 


1 




1981, Langston 1983, Anderson et al. 1981). A physiological 
or functional perturbation resulting from exposure to an 
environmental agent during a critical period of development 
may increase risk. Children may be more susceptible 
qualitatively, suffering adverse effects not experienced by 
adults, or quantitatively in that effects occur at a lower 
exposure level or are more severe at the same exposure level 
(Faith and Moore 1977). 

Children may be more vulnerable to specific 
environmental pollutants because of differences in absorption, 
metabolism, and excretion. Elevated rates of gastrointestinal 
absorption of nitrates in infants and lead in young children are 
well known. Percutaneous absorption is elevated during the 
first few days of life until keratinization of the skin occurs. Age- 
related differences in both the rates and the pathways of 
metabolism affect excretion rate and the half-life of a chemical 
in the body. Young children have higher resting metabolic and 
oxygen consumption rates than do adults. These higher rates 
are related to a child's rapid growth and larger cooling surface 
area per unit of body weight. Developmental regulation of 
metabolic pathways can result in the activation and 
deactivation of a pathway as individuals pass through life 
stages, affecting internal dosages (Bearer 1995). 

Children’s exposures to environmental pollutants are 
often different from those of adults because of different diets 
and different activities, such as playing on floors and in soil and 
mouthing of their hands, toys, and other objects, that can bring 
them into greater contact with environmental pollutants (Bearer 
1995). Because children consume proportionately more food 
and fluids, have a greater skin surface area relative to their 
body weight, and breathe more air per unit body weight than 
adults, they may receive greater exposure to environmental 
substances. For example, an infant weighs about one-tenth as 
much as a typical adult, but consumes about one-third as much 
water daily (Goldman 1995). The diets of infants and young 
children are very different from adult diets. Certain food types, 
such as juices, for example, can make up a larger proportion 
of the child’s diet, resulting in a higher exposure to pesticides 
(NRC 1993). 

The causes of most developmental effects and 
childhood diseases are unknown, but there is evidence that 
environmental agents play a role in some adverse outcomes. 
Exposure to environmental agents affecting development both 
in utero and postnatally can result in a wide array of adverse 
developmental endpoints, such as spontaneous abortions, 
stillbirths, malformations, early postnatal mortality, reduced 
birth weight, mental retardation, sensory loss, and other 
functional or physical changes (NRC 1993). Lead, 
methylmercury, polychlorinated biphenyls (PCBs), ethyl 
alcohol, and ionizing radiation have been implicated in human 
studies as causes of developmental effects (EPA 1991), while 
other chemicals have been implicated in animal studies. Lead 
and methyl mercury exposures in children are related to a 
variety of neurological problems that do not occur in adults 


exposed at comparable levels, including reading and learning 
disabilities, IQ deficiencies, impaired hearing, reduced attention 
spans, antisocial behavior, and hyperactivity. Prenatal and 
perinatal exposure to PCBs has been associated with delayed 
development and learning disabilities in children (Jacobson et 
al. 1990). 

Childhood exposure to air pollutants, including ozone, 
sulfur dioxide, particulate matter (PM), and nitrogen dioxide, 
has been associated with decreased lung function, increased 
incidence of bronchitis, increased respiratory illness, increased 
hospital admissions for respiratory causes, and exacerbation 
of asthma (Bates 1995). 

The self-reported prevalence rate for asthma 
increased 75% from 1980 to 1994, with the greatest increase 
occurring among children aged 0-4 years (160% from 22 per 
1,000 to 57.8 per 1,000) and aged 5-14 years (74% from 42.8 
per 1,000 to 74.4 per 1,000). The estimated annual number of 
physician office visits for asthma more than doubled from 4.6 
million to 10.4 million between 1975 and 1995 for all age, sex, 
and racial groups. Asthma-related hospitalization increased 
between 1979-80 and 1993-94, while the rate of 
hospitalizations remained constant. Hospitalization rates were 
consistently higher among African Americans. Children aged 
0-4 years had the highest hospitalization rate of any age group. 
Rates of death with asthma as the underlying cause decreased 
between 1960-62 and 1975-77 and then gradually increased. 
Most deaths occur in people over 65 (Mannino et al. 1995). 

Currently, the most important factor associated with 
asthma is a genetic susceptibility to become allergic. Indoor 
allergens including cockroaches, dust mites, and animal dander 
have been identified as the most common triggers of asthma 
symptoms. Environmental tobacco smoke, upper respiratory 
tract viral infections, ozone, sulfur dioxide, and PM have also 
been suggested as asthma triggers (Etzel 1995). 

In children, exposure to environmental tobacco smoke 
is causally associated with an increased risk of lower 
respiratory tract infections such as bronchitis and pneumonia, 
an increased prevalence of fluid in the middle ear, symptoms 
of upper respiratory tract irritation, small reductions in lung 
function, and additional episodes and increased severity of 
symptoms of asthma. Maternal smoking is considered a high 
risk factor for Sudden Infant Death Syndrome (EPA 1992). 

These examples show a relationship between 
exposure to environmental agents and adverse health effects 
in children. However, most causes of adverse developmental 
effects and the reasons for the increase in asthma rates in 
children are unknown. It has been hypothesized that the 
thousands of man-made chemicals introduced into the 
environment in recent years, most of which have not been 
tested for developmental effects, may be precipitating or 
contributing factors in some cases. Another unknown is the 
extent to which the biologically effective dose differs between 


2 



children and adults. The response to a chemical could be 
identical for children and adults at a given dose at the target 
site, but a child could receive a higher dose than an adult in the 
same environment. These uncertainties make it difficult to 
answer the question of whether EPA’s health-based standards 
are protective of children, and they provide the impetus for a 
research program on children’s health. 

1.3. Research Questions 

This strategy outlines a research program that will 
address questions about children’s vulnerabilities to adverse 
effects from exposure to environmental agents, the quantitative 
risk from exposure to environmental agents, and how the risk 
can be reduced. The following research questions are 
addressed in the strategy: 

1. What are the adverse effects from children’s 
exposures to environmental agents that are qualitatively or 
quantitatively different from effects in similarly exposed adults? 
What are the near-term and delayed effects of childhood 
exposures? What are the characteristics of the environmental 
agents associated with these effects? 

2. What are the specific periods of development when 
exposure to environmental substances can cause adverse 
health effects? 

3. What are the best in vitro models and in vivo 
animal models for screening for and identifying hazards to 
children? 

4. To what environmental substances are children 
more highly exposed? How do exposures differ with age? 
What factors contribute to higher exposures? 

5. What are the relationships between exposures to 
children and adverse health effects observed in childhood or 
later? What factors in the child’s environment can increase 
risks? 

6. How can laboratory and human data be used to 
predict responses to childhood exposures? 

7. What is the variation in exposure and susceptibility 
within members of the same age group, and what are the 
factors that contribute to this variation? 

8. What are the adverse effects from children’s 
exposures to mixtures that are quantitatively or qualitatively 
different from effects in similarly exposed adults? 

9. What are the uncertainties in estimating 
environmental risks to children and how can they be 
characterized in risk assessment? What are the most effective 
methods for communicating results, data, and risks to risk 


assessors, risk managers and the public? 

10. What are the specific agents and pathways of 
exposure where risk management research will be effective in 
addressing known risks to children? What are the most 
effective methods for reducing environmental risks to children? 

1.4. Goals and Objectives 

This strategy was developed within the framework 
established in the EPA and ORD strategic plans (EPA 1997b, 
c). EPA developed its strategic plan in compliance with the 
Government Performance and Results Act (GPRA) passed by 
Congress in 1993. The EPA strategic plan lists ten broad 
GPRA goals that serve as a framework for EPA’s planning and 
resource allocation. This strategy addresses Goal 8: Provide 
sound science to improve the understanding of environmental 
risk and develop and implement approaches for current and 
future environmental problems. The EPA program has been 
arrayed under the GPRA goals as a series of objectives, 
subobjectives, and annual milestones for purposes of reporting 
under GPRA. The ORD Children’s Health program, which is 
the topic of this strategy, 's part of the ORD Sound Science 
program in Human Health Risk Assessment under Goal 8. The 
objectives of this strategy are shown in Figure 1. 

1.5. ORD Research Strategies and 
Plans 

The ORD strategic plan identifies six high-priority 
research topics: safe drinking water (with a near-term focus on 
microbial pathogens, disinfection by-products, and arsenic), 
high-priority air pollutants (with a near-term focus on particulate 
matter), emerging environmental issues (with a near-term focus 
on endocrine disruptors), research to improve ecological risk 
assessment, research to improve human health risk 
assessment, and pollution prevention and new technologies for 
environmental protection. Research strategies are being 
developed for the six high-priority areas and for specific 
subtopics (see Appendix B), including children’s health. ORD 
is developing a strategy for research on asthma, which will 
include research on childhood asthma (EPA 2000a). 

1.6. Organization 

Section 2 provides a brief overview of the risk 
assessment/risk management framework within which ORD 
organizes its human health risk assessment research and a 
discussion of new directions in risk assessment. Section 3 
discusses the legislative, regulatory, and policy decisions that 
encouraged development of the strategy and the relevant EPA 
Program and Regional Office activities. Section 4 summarizes 
research recommendations from many sources, and outlines 
the research program. Section 5 presents guidance for 
implementation. 


3 





Figure 1. Objectives of the ORD Strategy for 
Research on Environmental Risks to Children 

■ Establish direction for a long-term, stable core research program in children’s environmental health that leads to 
sustained risk reduction through more accurate, scientifically based risk assessments for children. 

■ Identify research to answer the key questions about children’s environmental health risks and increase our 
understanding of when children respond differently from adults to toxic agents and why. 


■ Identify research that will help to reduce children’s risks. 

■ Provide a research agenda that identifies research priorities for the ORD intramural and extramural research 
programs. 

■ Inform EPA scientists, risk assessors, and risk managers of the research related to children at EPA and other Federal 
agencies. 


Provide guiding principles for implementation. 


4 



2. APPROACHES TO RISK ASSESSMENT 


This strategy was developed within the framework of 
the risk assessment-risk management paradigm proposed by 
the National Academy of Sciences (NRC 1983) and covers a 
wide range of topics and disciplines. Readers will have varying 
degrees of familiarity with the use of quantitative risk 
assessment to support environmental risk management 
decisions. A brief description of the EPA risk assessment 
process is presented here to help readers understand the 
potential impact of the research outlined in this strategy on 
EPA programs. 

Risk assessment is the process used to evaluate the 
hazards of and exposures to environmental agents to produce 
estimates of the probability that populations or individuals will 
be harmed and to what degree. It is one component of the 
process by which EPA and many other organizations recognize 
a potential risk and decide how to respond. Risk assessment 
has been defined by the National Academy of Sciences (NAS) 
to consist of four steps: hazard identification, exposure 
assessment, dose-response assessment, and risk 
characterization (NRC 1983). 

The hazard assessment describes the likelihood that 
an environmental agent will produce adverse effects and the 
mechanisms by which agents exert their toxic effects. The 
exposure assessment specifies populations that might be 
exposed, identifies routes of exposure (usually inhalation, 
ingestion, and dermal contact), and estimates the magnitude, 
duration, and timing of the doses received. The exposure 
assessment may also determine the sources of exposure and 
the contribution of each source to the total exposure. The 
dose-response assessment describes the relationship between 
dose level and degree of toxic response. The risk 
characterization integrates information from the first three steps 
to develop estimates of the likelihood that any of tne identified 
effects will occur in exposed people (NRC 1994). 

2.1. The Standard Regulatory 
Approach 

The standard regulatory risk assessment of an 
environmental agent is organized according to the four steps 
of the NAS paradigm and is based on the available data most 
relevant to the population being evaluated. If population- 
specific data are not available and cannot be collected, 
extrapolation methods and default assumptions are used to 
complete the assessment. 3 


3 EPA assessment methods are described in a series 
of assessment guidelines for exposure and cancer and 
noncancer endpoints (e.g., EPA 1996b, EPA 1996c, EPA 
1991). 


The exposure assessment links environmental and 
personal exposure measurements with activity patterns using 
exposure models to estimate dose. Exposure models may be 
as simple as an estimate of inhalation dose as the product of 
concentration, breathing rate, and time of exposure. Or they 
may be complex, with many exposure pathways and dozens of 
variables. Understanding the sources of exposure and how the 
environmental agent is transported from its sources to the 
exposed individual may be critical to estimating concentrations 
in the air, water, soil, dust, and food to which individuals are 
exposed. It is also important to know the sources of exposure 
in order to identify, evaluate, and implement risk management 
options. 

Estimates of exposure or dose from the exposure 
assessment are combined with information on toxic response 
to produce estimates of risk. The process for determining the 
likelihood of an adverse effect at a particular exposure or dose 
is the dose-response assessment. Human data suitable for 
developing dose-response relationships are usually obtained 
from groups that have been highly exposed in the workplace, 
by accident, through diet, and the like. Studies of groups 
outside the United States that have been historically exposed 
to high levels of environmental pollution are sometimes used. 
Even when such highly exposed groups exist, however, the 
difficulty in determining and quantifying individuals’ exposure 
histories as well as the presence of other possible causes of 
the adverse effect can prevent even the observation of a 
cause-effect relationship. Therefore, the quantitative dose- 
response assessment is usually based on data from controlled 
laboratory studies where effects on animals are evaluated and 
the results extrapolated to humans. 

Under the current EPA default approach to hazard 
and dose-response assessment, cancer is thought of as the 
consequence of chemically induced DNA mutations. Because 
a single chemical-DNA interaction may lead to a mutation and 
since cancer is thought to arise from single cells, any dose, no 
matter how low, is assumed to have the potential to cause the 
adverse effect. This is referred to as a nonthreshold effect. 
Nonthreshold effects are modeled as linear relationships 
between response and dose across the entire dose-response 
curve. Dose-response relationships observed at the relatively 
high doses administered in the laboratory are assumed to hold 
true at the lower doses usually experienced by humans in the 
environment (ERG 1997, 1998). 

Effects other than cancer (threshold effects) have 
been assumed to result from multiple chemical reactions within 
multiple cells. EPA’s policy is to assume that, for noncancer 
effects, there is a safe exposure, and that no adverse effects 
are likely to occur below that threshold. The threshold is 
estimated based on the highest exposure at which no effect 
was observed in an experimental study--the NOAEL (no- 


5 




observed-adverse-effect level) or the NOEL (no-observed- 
effect level) (NRC 1994). To establish a safe limit for human 
exposure, the NOAEL is divided by uncertainty factors to 
account for differences in susceptibility among humans, 
differences between test species and humans, and other 
uncertainties resulting from lack of key data such as a long¬ 
term dosing study or a NOAEL. A typical assessment uses a 
factor of 10 to account for variability in human response and a 
factor of 10 to account for interspecies differences. At EPA, 
this quotient is termed Reference Dose (RfD) when derived for 
ingestion exposure and Reference Concentration (RfC) for 
inhalation exposure (NRC 1994). 

The standard regulatory approach is extremely useful 
in that it has allowed EPA to assess and make regulatory 
decisions on thousands of chemicals, often with limited data, 
while providing some assurance that the decisions are 
protective of public health. However, questions often arise 
about whether the current approaches accurately account for 
the many uncertainties introduced when assessments are 
based on data from the laboratory. Available dose-response 
data must be extrapolated from the high exposures used in 
laboratory experiments to the lower exposures usually found in 
the environment. The internal dose to the target tissue in 
humans is usually unknown. The frequency and duration of 
exposure in the laboratory study is often different from what 
can be expected in the environment. It is often difficult to find 
an appropriate animal model forthe substance and endpoint of 
concern or to predict differences in the magnitude of the 
response between animals and humans. There is a major 
difficulty in extrapolating from immature laboratory animals to 
children because growth rates and the level of development 
and maturation of organs and systems at and after birth can be 
considerably different across animal species, as well as 
between animals and humans. Current default approaches do 
not easily allow for incorporation of all relevant data in the 
dose-response assessment. Factors that can cause significant 
age-related differences in exposure and toxicity, such as 
metabolic pathways and rates, distribution in the body, dose to 
target organ, excretion, DNA repair, and growth and cell 
proliferation are not accounted for except through uncertainty 
factors. 

2.2. Future Directions in EPA Risk 
Assessment 

The exposure-dose-response relationship can be 
envisioned as a continuum of events in which exposure to a 
substance occurs, the substance enters and moves through 
the body and may be chemically transformed, and interacts to 
cause changes in molecules, cells, and tissues, leading to 
disease. The series of events by which a substance exerts its 
toxic effects is referred to as a mechanism of action. The term 
“mechanism of action” will be used here to refer to the 
complete sequence of biological events that must occur to 
produce the adverse effect. Typically, only partial information 


on the mechanism of action is available. In such a case the 
term “mode of action” will be used to refer to mechanisms for 
which some but not all of the steps are known. In many cases, 
exposures and early effects in the biological sequence can be 
measured through biological markers. An assessor is often 
able to describe qualitatively many of the processes that lead 
from exposure to effect, but lacks the data and methods to use 
the information in the quantitative risk assessment. 

Better understanding of the sequence of events 
leading to adverse effects and availability and use of biological 
data will increase EPA’s ability to assess risks. Early biological 
effects are more prevalent in the population than is actual 
disease, and biomarkers of early effects may sometimes be 
more specific to environmental agents. A better understanding 
of the pharmacokinetics and toxic modes of action of 
environmental agents will improve hazard identification and 
reduce uncertainties in extrapolation from laboratory 
measurements of the dose-response relationship to events in 
the environment (eg., see EPA 1996b). Expanded 
development and use of biological data is essential to 
quantifying variability in human susceptibility, understanding 
responses to mixtures of chemicals, and harmonizing risk 
assessment methods for cancer and noncancer endpoints. 

One method of incorporating information on the mode 
of action in the dose-response assessment is the use of 
biological models. Physiologically based pharmacokinetic 
(PBPK) models address the exposure-dose relationship in an 
organism taken as a whole, estimating the dose to a target 
tissue or organ by taking into account rates of absorption into 
the body, metabolism, distribution among target organs and 
tissues, storage, and elimination. Biologically based dose- 
response (BBDR) models describe specific biological 
processes at the cellular and molecular levels that link the 
target-organ dose to the adverse effect (Faustman and Omenn 
1996). PBPK and BBDR models are useful in extrapolating 
between animals and humans and between children and adults 
because they allow consideration of species- and age-specific 
data on physiological factors affecting dose levels and data on 
biological responses that are different or more intense in 
children. 

With advances in the ability to measure and model the 
biological events in the exposure-dose-response continuum, 
the science of risk assessment is moving toward a 
harmonization of the methodology of cancer and noncancer 
assessments and away from a consideration of endpoints in 
isolation. Carcinogenesis is now recognized to embody 
changes in key genes that regulate the cell replication cycle 
and that can be influenced by mutagenic and nonmutagenic 
modes of action. When direct mutagenic events do not pertain 
and other modes of action apply, the likelihood exists that 
cancer is secondary to other events (e.g., stimulation of cell 
division) and that a potential for cancer exists only at doses 
sufficient to produce the events. Thus, in some cases, 
thresholds could apply. Conversely, it is now recognized that 


6 



threshold considerations may not apply to all noncancer 
effects. For example, effects of lead exposure are manifested 
at existing environmental exposure levels, and no apparent 
NOAEL exists (ERG 1997, 1998). 

Thus, the current scientific database indicates that 
automatic separation of dose-response relationships for cancer 
and noncancer effects may not be justified. A focus on modes 
of action of carcinogenesis directs attention away from tumors 
toward earlier biological and toxicological responses critical in 
the carcinogenesis process. Such responses are relevant to 
both cancer and noncancer effects and serve as a bridge to 
link their risk assessments. Use of biological data and 
harmonization of assessment methods may also provide new 
means by which to study relationships between environmental 
agents and rare endpoints such as the various childhood 
cancers. If it could be demonstrated, for example, that 


childhood cancer and birth defects of a particular target organ 
result from similar modes of action, these endpoints might be 
combined in an epidemiology study. The higher percentage of 
cases in the population resulting from combining cases 
involving different endpoints would increase the ability to 
observe relationships between the adverse effects and 
exposure to environmental agents hypothesized to produce the 
effects by the common mode of action. 

New directions in risk assessment at EPA also 
include more emphasis on total exposure via all pathways, 
consideration of cumulative risks when individuals are exposed 
to many chemicals at the same time, and use of probabilistic 
modeling methods such as Monte Carlo analysis to provide 
better estimates of the range of exposure, dose, and risk in 
individuals in the population. 


7 



3. IMPLEMENTATION OF LEGISLATION AND POLICY ON 
CHILDREN’S ENVIRONMENTAL HEALTH 


In 1996, Congress enacted two statutes requiring that 
EPA consider children and other potentially susceptible groups 
when setting health-based standards: the Food Quality 
Protection Act of 1996 (FQPA) and the Safe Drinking Water Act 
(SDWA) Amendments of 1996. 

Because of the risk assessment requirements in 
FQPA, EPA’s Office of Pesticide Programs (OPP) is very 
active in addressing children’s risk issues. FQPA calls for a 
reassessment of pesticide tolerances and registrations to 
ensure that they are protective of children. The statute 
provides that in making a finding of reasonable certainty of no 
harm for threshold effects, “an additional tenfold margin of 
safety for the pesticide chemical residue and other sources of 
exposure shall be applied for infants and children to take into 
account potential pre- and postnatal toxicity and completeness 
of data with respect to the exposure and toxicity of infants and 
children.” The Administrator may use a different margin of 
safety “only if, on the basis of reliable data, such margin will be 
safe for infants and children" (FQPA, section 405, amending 
the Federal Insecticide, Fungicide, and Rodenticide Act, 
section 408(b)(2)(C)). 

OPP has developed a draft policy on application of the 
tenfold margin of safety (the 10X Factor) (EPA 1999a), which 
identifies a core set of toxicity tests that will be accepted as a 
complete toxicity database for infants and children. OPP will 
consider the completeness of the toxicity data as part of RfD 
development. If one or more of the key studies in the core is 
missing or inadequate, an Uncertainty Factor for database 
uncertainty will be used in deriving the RfD. Decisions on the 
completeness of the exposure database will be made as part 
of the exposure assessment, based on whether sufficient data 
exist either to accurately determine exposure or to assure that 
exposures to infants and children are not underestimated. If for 
some reason, the RfD process does not consider all possible 
uncertainties related to toxicity, residual uncertainties will be 
considered in the risk characterization. 

The final decision on the 10X Factor will be made by 
considering together the use of Uncertainty Factors to account 
for database uncertainty and potential toxicity to infants and 
children in developing the RfD, the recommendations in the 
exposure assessment regarding the need to account for 
incompleteness in the exposure database, and any residual 
uncertainties and concerns identified in the risk 
characterization. On the weight of the evidence, OPP may 
decide to retain the 10X Factor, or remove, reduce, or raise it. 4 


4 There are many important issues related to the FQPA 
Safety Factor that cannot be addressed here. OPP may 
change some parts of its draft policy before it is finalized. The 


ORD supported OPP’s development of toxicity and 
exposure data requirements for the 10X Factor through 
leadership of and participation in EPA working groups 
addressing these issues (EPA 1999b, c). The FQPA data 
requirements were considered in developing this strategy. 

In other activities related to implementation of FQPA, 
OPP has developed standard operating procedures for 
assessing exposure by multiple routes (Versar 1997) and 
methods for conducting aggregate exposure and risk 
assessments (EPA 1999d). These methodologies consider 
dietary and drinking water exposures using intake values for 
young age groups. They also consider such childhood 
exposure pathways as contact with dust and soil followed by 
ingestion, exposure to pesticides on toys, and ingestion of 
pesticide pellets. 

The SDWA Amendments of 1996 require that EPA 
take into account the effect of contaminants on sensitive 
subpopulations, including infants and children, when deciding 
which drinking water contaminants present the greatest public 
health concerns and whether to regulate contaminants. Office 
of Water activities are focused on protecting infants and 
children from contaminants such as microbes and chemicals in 
drinking and recreational water and fish. The Drinking Water 
Health Advisory program develops guidance for short-term 
exposures to drinking water contaminants to protect children 
against noncancer health effects. 

In addition to implementing these statutes, EPA has 
a policy of specifically considering children throughout its 
programs. U.S. Executive Order No. 13045 requires that each 
Federal agency shall make it a high priority to ensure that its 
policies, programs, activities, and standards address 
disproportionate risks to children that result from environmental 
health risks or safety risks (US Executive Order No. 13045 
1997). In 1995, the EPA Administrator established a policy to 
explicitly take into account health risks to children and infants 
from environmental hazards when conducting assessments of 
environmental risks (EPA 1995a). The announcement of the 
policy was followed by a 1996 EPA Administrator’s report, 
Environmental Health Threats to Children and EPA’s National 
Agenda to Protect Children’s Health from Environmental 
Threats (EPA 1996a). The National Agenda calls for an 
evaluation of all EPA standards to ensure sufficient protection 
for children, expansion of scientific research on childhood 
susceptibilities and exposures, and an emphasis on outreach 
to parents and communities through education and other 
measures to reduce and prevent childhood risks. All EPA 


latest information can be found at the Internet site of the OPP 
Science Advisory Panel: http://www.epa.gov/scipoly/sap/ 


8 






Program Offices and Regions have programs to implement 
these policies. 

OPPTS is authorized by statute to require 
manufacturers to test new and existing pesticides and other 
toxic substances and submit data for evaluating safety. Much 
of the toxicity testing in the United States is performed by the 
private sector under the Toxic Substances Control Act (TSCA). 
OPPTS provides test protocols and recently issued an updated 
set of testing guidelines that will provide better information on 
health effects in children, particularly reproductive and 
developmental effects. Guidelines have been updated and 
expanded to include chemical effects on metabolism, 
developmental neurotoxicity, and reproductive and prenatal 
developmental toxicity (EPA 1998a). New guidance is 
provided for testing for toxic effects on the immune system. 

Part 50 of the Clean Air Act and its supporting 
legislative history require that EPA establish National Ambient 
Air Quality Standards (NAAQS) to protect the health, with an 
adequate margin of safety, of susceptible subpopulations. The 
innate developmental and physiologic characteristics and the 
activity patterns leading to higher exposures that make children 


susceptible to these air pollutants have been considered in 
every NAAQS promulgated under the Clean Air Act. 

The Office of Solid Waste and Emergency Response 
(OSWER) routinely considers children’s exposure at waste 
sites through dermal contact and ingestion of contaminants in 
dust and soil. OSWER is expanding its efforts through such 
actions as conducting consistent, comprehensive assessments 
to evaluate the impact on children of lead-contaminated 
hazardous waste sites. 

The EPA Regional Offices are leading and 
participating in outreach, risk assessment, risk intervention, 
and community educational projects, often in cooperation with 
State and local governments, private organizations such as the 
American Lung Association and the Parent-Teacher 
Association, and members of local communities. The Regions 
address important environmental problems, including children’s 
risks from proximity to hazardous waste sites, asthma in 
children and its relationship to allergens and other 
contaminants in indoor environments, and lead and pesticides 
in residences. 


9 



4. RESEARCH DIRECTIONS 


In developing this strategy, the science team followed 
the approach outlined in the ORD Strategic Plan (EPA 1997c). 
Research recommendations of conferences, workshops, and 
scientific reports on children’s environmental health were 
reviewed. Comments were sought from the ORD national 
laboratories and centers. The ORD Science Council, 
composed of the ORD Deputy Assistant Administrator for 
Science, the ORD Associate Directors for Health and Ecology, 
and other ORD science managers, was consulted. EPA 
Program Offices and the Office of Children’s Health Protection 
(OCHP) contributed recommendations through membership on 
the science team. The science team formulated the set of 
research questions in Section 1.3 and a set of research areas 
to address the questions. Criteria were developed and the 
research areas were assigned a priority of high, medium, or 
low. Section 4.1 discusses research needs and 
recommendations. Section 4.2 summarizes current research 
sponsored by EPA and other Federal agencies. Section 4.3 
describes possible research areas for the ORD Children’s 
Health program, the feasibility of conducting the research at 
EPA, and the priority of the research. Section 4.4 discusses 
the impact of the research on risk assessment and 
management and the relationships between the research 
areas. 

4.1. Research Needs and 
Recommendations 

Over the past two decades, many groups of experts 
have considered how exposure to environmental agents affects 
children. Hundreds of research issues have been defined, 
addressing numerous age groups, disease endpoints, 
biomarkers of disease, modes of action, exposure pathways, 
environmental agents, physiological and biological 
characteristics affecting dose, and methods of risk 
communication and risk reduction. Research on children’s 
environmental health is performed by members of many 
disciplines, among whom are physicians; classical and 
molecular epidemiologists; developmental toxicologists, 
including specialists in neurotoxicity, immunotoxicity, and 
childhood cancer; environmental scientists; engineers; and 
statisticians. 

The sources of research recommendations 
considered by the science team and the topic areas covered 
are shown in Table 1 and Appendix C. 

4.2. Current Research 

ORD conducts research on exposures to 
environmental agents and related adverse effects in children. 
Other Federal agencies also study the occurrence and causes 
of childhood developmental disorder and disease. The Federal 


public health agencies of the Department of Health and Human 
Services, especially the National Cancer Institute (NCI), the 
National Institute of Environmental Health Sciences (NIEHS), 
the National Institute of Allergy and Infectious Disease (NIAID), 
the National Institute for Child Health and Human Development 
(NICHD), and the Centers for Disease Control and Prevention 
(CDC), support much of the Federal research, surveillance, 
and data collection on children’s health in the United States. 
Although much of this research is relevant to EPA’s mission, 
only a fraction of the Federal program investigates the specific 
role of environmental agents in causing adverse effects in 
children. This section describes some of the Federal programs 
directed at children’s environmental risks and gives examples 
of projects underway at EPA. The Children’s Environmental 
Health and Safety Inventory of Research (CHEHSIR), which is 
available via the Internet (EPA 2000b), reports relevant Federal 
research at the project level. Appendix D describes the roles 
of the Federal research programs that are most relevant to 
children’s environmental health. 

4.2.1. National Testing Programs 

The Federal Government develops testing protocols 
and tests pesticides and other chemicals in animals to identify 
potential hazards to humans. Under programs administered by 
OPPTS (Section 3), EPA may require manufacturers to test 
substances in commerce to identify those that may be 
hazardous to human health. ORD supports the OPPTS testing 
program through research in improved methods of chemical 
testing. The National Toxicology Program (NTP) also conducts 
toxicity testing. NTP consists of relevant activities of NIEHS, 
the National Institute of Occupational Safety and Health 
(NIOSH), and the U.S. Food and Drug Administration (FDA). 
NTP develops and conducts in vitro and in vivo tests for long¬ 
term carcinogenesis, reproductive and developmental effects, 
genotoxicity, teratogenicity, immunotoxicity, neurotoxicity, and 
other disease endpoints. NTP is responsible for one-third of 
all toxicity testing performed world-wide (NIEHS 2000a). EPA 
is a voting member of the Interagency Testing Committee 
(ITC), through which chemicals are nominated and selected for 
NTP toxicity testing. 

4.2.2. Modes of Action and Modeling of 
Physiological/Biological Processes 

In addition to routine chemical testing to identify 
substances of concern, the Federal Government sponsors 
research to investigate the biological processes by which toxic 
effects, including effects in children, occur. ORD is developing 
methods to evaluate hazards for noncancer human health 
endpoints, including new and refined test methods for 
neurotoxicity, immunotoxicity, and reproductive toxicity, and 
predictive models to improve the biological basis for human 


10 



Table 1. Research Recommendations and Needs 

Source 

Description 

Topic Areas 

ILSI (1992) 

•EPA-sponsored workshop conducted by 
International Life Sciences Institute (ILSI): 
Similarities and Differences Between 
Children & Adults 
•Invited investigators 

•Development and genetics 

•Physiological and biochemical differences between 

children and adults 

•Animal models for developmental toxicology 
•Age-related responses in cancer bioassays 
•Drug case studies 

•Environmental case studies (ionizing radiation, lead, 
vinyl chloride, polyhalogenated biphenyls) 

•Pesticide case studies 

NRC (1993) 

•NRC panel report: Pesticides in the 

Diets of Infants and Children 

•Differences between infants, children, and adults 
•Selection of appropriate animal models 
•Toxicity 

•Methods of toxicity testing 
•Food and water consumption 
•Estimating exposures 
•Estimating risks 

ILSI (1996) 

•EPA-sponsored workshop: Research 
Needs on Age-related Differences in 
Susceptibility to Chemical Toxicants: 

Report of an ILSI Risk Science Institute 
Working Group 
•Invited experts 

•Cancer 
•Neurotoxicity 
•Immune system effects 

CEHN (1997) 

•Children’s Environmental Health Network 
conference: 1 st National Research 
Conference on Children’s Environmental 
Health: Research, Practice, Prevention, 
Policy 

•Invited speakers 

•Asthma and respiratory effects 
•Childhood cancer 
•Neurodevelopmental effects 
•Endocrine disruptor effects 
•Exposure 

•Risk prevention and reduction through community 
involvement and education 

EPA (1998b) 

•EPA interim final guidance: Guidance for 
Considering Risks to Children During 
Establishment of Public Health-Related 
and Risk-Related Standards 

•Hazard considerations 
•Dose-response/susceptibility considerations 
•Exposure considerations 

EPA (1998c) 

•EPA-sponsored conference: 

Preventable Causes of Cancer in Children 
•Invited speakers 

•Epidemiology & prevention of childhood cancer 
•Susceptibility factors for childhood cancer 
•Molecular markers of exposure and effect for 
childhood cancer 

•Quantitative measurement of exposure to potential 
childhood cancer agents 

NRDC (1997) 

•National Resources Defense Council 
report: Our Children at Risk: the 5 Worst 
Environmental Threats to Their Health 

•Lead 

•Air pollution 
•Pesticides 

•Environmental tobacco smoke 
•Drinking water contamination 


11 













Table 1. Research Recommendations and Needs (continued) 

Source 

Description 

Topic Area 

EPA (1998d) 

•EPA workshop: Assessment of Health 
Effects of Pesticide Exposure in Young 
Children 

•Invited experts from many disciplines 
•Focus on identification of health effects 
associated with exposure to pesticides 
and how to measure those effects in 
children 

•Neurotoxicity 
•Developmental toxicity 
•Carcinogenicity 
•Immunological effects 
•Respiratory effects 

EPA (1998e) 

•Annual EPA Regional risk assessor's 
meeting: session on risk assessment 
issues related to children’s health 

assessments 

•EPA Regional risk assessors and 
interested EPA Program Office and ORD 
representatives 

•Consistent approaches to toxicity assessment for 
children 

•Consistent approaches to exposure assessment for 
children 

•Default assumptions for children’s risk assessments in 
absence of data 

•Childhood cancer and childhood exposure resulting in 
adult cancer 

•Effects of children’s exposure to mixtures 

•Risk communication to the public on children’s issues. 

EPA 10X Task 

Force (EPA 1999a, 
b, c) 

•Task Force reports providing 
recommendations on application of FQPA 
10X Factor: 

-Toxicology Data Requirements for 
Assessing Risk of Pesticide Exposure to 
Children's Health 

- Exposure Data Requirements for 
Assessing Risk from Pesticide Exposure 
of Children 

- The Office of Pesticide Programs 

Policy on Determination of the 

Appropriate FQPA Safety Factor(s) for 

Use in the Tolerance Setting Process 

•Toxicity 

•Exposure 

•Integration (decisionmaking on 10X Factor based on 
all toxicity and exposure considerations) 

U.S. Task Force 
established under 
Executive Order 
13045 

•U.S. Task Force established four working 
groups to develop Government-wide 
initiatives for FY2000 on children’s 
environmental health and safety issues 

•Developmental disorders 
•Childhood cancers 
•Childhood asthma 
•Unintentional injury 


health risk assessment. This research includes pesticide- 
specific studies to determine long-term health effects of 
exposures during development. At issue are reproductive 
competency and function, neurobehavioral changes, 
neurochemistry, neural growth and differentiation, allergic 
response, and immune function. Some of the ongoing studies 
attempt to understand and characterize the mechanisms by 
which toxicants interact at the cellular and molecular levels to 
produce adverse effects. As we obtain more data on these 
modes of action, we will be able to test the assumptions 
underlying our risk assessment methodologies and to develop 
new methods that will more accurately predict children’s risks. 
Research in the pharmacokinetics of toxicants and modes of 
toxic action are providing results that will help develop PBPK 
and BBDR models for target organs (eg., respiratory, 


reproductive, and nervous systems) leading to improved 
hazard identification and methods of extrapolation between 
animals and humans. 

The ORD extramural grants program, Science To 
Achieve Results (STAR), is supporting grants to investigate the 
biological and physiological characteristics of different age 
groups, variability in response within particularage groups, and 
the biological basis for instances of increased susceptibility to 
environmental contaminants in children. 

At ORD’s National Health and Environmental Effects 
Research Laboratory (NHEERL), batteries of cellular and 
molecular markers, as well as functional tests, are being 
developed to aid in the identification and characterization of 


12 












toxicant-induced alterations in the ontogeny of the 
reproductive, immune and central nervous systems. Studies 
are underway to determine if there are long-term, persistent, or 
latent effects in animals exposed to environmental toxicants 
during development and, if so, to identify the mechanisms 
responsible for these effects. Scientists at NHEERL are also 
investigating the toxicodynamic and toxicokinetic mechanisms 
that underlie age-dependent responses to toxicants. 

NIEHS’s research program is closely allied with that 
of ORD in studying the impact of environmental contaminants 
on public health. Under their extramural programs, EPA and 
NIEHS jointly sponsor eight Centers for Children’s 
Environmental Health and Disease Prevention Research (EPA 
2000c). The centers conduct research to improve detection, 
treatment, and prevention of environmentally related diseases 
in children. The NIEHS Intramural Division conducts basic and 
applied research on how environmental exposures affect 
biological systems and human health, on the identification of 
susceptible subpopulations, and on the interaction between the 
environment, genes, and age. NIEHS is sponsoring the 
Environmental Genome Project, which will investigate the 
interaction of genes and environmental contaminants in 
causing human disease (NIEHS 2000b). The role of gene- 
environment interactions on human development and childhood 
disease could be studied under the Environmental Genome 
Project. 

NCI is the primary sponsor of research on the biology 
of cancer. Investigations are focused on identifying and 
understanding the genes whose activity allows DNA changes 
that result in a normal cell becoming a cancer cell. NCI is 
developing and using experimental biological models that 
mimic the wide variety of human cancers (NCI 2000). 

NICHD supports research on the reproductive, 
neurobiological, developmental, and behavioral processes that 
determine and maintain the health of children and adults 
(NICHD 2000). The NICHD program includes research on the 
effects of exposure to environmental agents on human 
development. In 1999, EPA and NICHD sponsored a Request 
for Applications (RFA) for research on genetic susceptibility 
and variability of human malformations. EPA's efforts in this 
area focus on identifying environmental agents that cause birth 
defects and other developmental disorders, the molecular 
mechanisms of birth defects, and how to use mechanistic and 
other data in the risk assessment process (EPA 2000c). 

4.2.3. Studies in Human Populations 

Five of the EPA/NIEHS-sponsored Centers for 
Children’s Environmental Health and Disease Prevention are 
studying the influence of the environment on asthma and other 
respiratory diseases in groups of children hypothesized to be 
highly exposed to airborne contaminants and devising ways to 
prevent or reduce exposures where necessary. ORD is 
participating in the Inner-City Asthma Study, a prevention trial 


led by NIAID aimed at developing intervention methods to 
reduce high asthma morbidity in inner-city children and 
adolescents. The Inner-City Asthma Study identified factors 
associated with asthma severity, including high levels of indoor 
allergens, high levels of smoking among family members and 
caretakers, and exposure to high levels of nitrogen dioxide, a 
respiratory irritant (Fauci 1997). 

Some studies are conducted in cities where high 
levels of air pollution increase the ability to observe 
relationships between pollutants and respiratory effects. ORD 
is studying the relationship between air pollution and children’s 
respiratory health in four Chinese cities. An ORD study is also 
underway to determine whether children are more susceptible 
than adults to nasal metaplasia and whether biochemical tests 
can detect morphological alterations caused by high ambient 
ozone and PM 10 pollutants in Mexico City (EPA 2000b). 

Three of the EPA/NIEHS Centers for Children’s 
Environmental Health and Disease Prevention are examining 
the relationship between developmental disorders and 
exposure to neurotoxicants such as organophosphate 
pesticides in groups of children believed to be highly exposed. 
ORD is also sponsoring studies of children’s exposures to 
pesticides in Minneapolis-St. Paul under the National Human 
Exposure Assessment Survey (NHEXAS); along the U.S.- 
Mexico border in Arizona and Texas; and under STAR grants 
in Arizona, Washington State, and Minnesota. Depending on 
the study, measurements include levels of pesticides in air, 
water, food, dust, and soil; personal biomarkers of exposure 
such as pesticide levels in blood, breath, and urine; and activity 
information (questionnaire, diary, observation, and 
videotaping). Some of these studies will focus on total 
exposure, sources of exposure, and differences in exposure 
between children and adults, and some also investigate the 
relationship between exposure and health endpoints. 

ORD has recently begun to investigate exposure of 
pre-elementary school children to persistent organic 
compounds through ingestion, inhalation, and dermal contact. 
Targeted compounds include polycyclic aromatic 
hydrocarbons, pesticides, phthalate esters, phenols, and 
polychlorinated biphenyls. Environmental samples will be 
collected in homes, classrooms, and outdoor play areas. 
Children will be videotaped to determine activity patterns and 
urine samples will be collected. Children and adult caregivers 
in approximately 450 households will be studied. 

ORD and CDC are supporting a number of studies to 
evaluate health and environmental conditions along the U.S.- 
Mexico border in the context of risk to children. The goals of 
one such study are to determine whether children are at 
increased risk of adverse health effects from exposure to 
pesticides, to identify risk factors, and to develop intervention 
and prevention strategies. Another study deals with the 
identification of lead exposure sources and risk reduction. 
Associations between ambient air quality and acute pediatric 


13 



respiratory health are being evaluated in a retrospective 
epidemiologic study. A case-control study of risk factors for 
neural tube defects is underway. The potential association of 
neural tube and cardiac defects and exposure to disinfectant 
byproducts in drinking water is also under examination. A 
separate study in Chile is investigating the relationship of 
chronic arsenic exposure in drinking water to congenital 
abnormalities and fetal, neonatal, and maternal morbidity and 
mortality. 

Examples of other current ORD studies include 
determination of the ability to link recent pesticide exposure 
and elevated cholinesterase levels to defined 
symptomatologies of young children in agricultural 
communities; evaluation of arsenic metabolic profiles in 
children and adults in order to determine if differences in 
metabolism are age-related or are due to differences in 
ingestion habits; and application of test methodologies for 
evaluating associations between estimated insecticide 
exposure and immunologic, developmental, and enzymatic 
endpoints. 

Many Federal agencies conduct surveillance of 
childhood disease and sponsor population-based studies of 
exposure and disease in children. These programs produce 
data and results vital to EPA’s risk-based programs. CDC’s 
National Center for Environmental Health (NCEH) tracks 
asthma emergency room visits, asthma hospitalizations, and 
asthma mortality on a national level and in four geographic 
regions in partnership with State and local governments. 
Hospitals and clinics routinely report obvious birth defects. 
NCEH surveys children aged 3 to 10 in metropolitan Atlanta to 
document developmental disabilities that require time to 
appear, including mental retardation, vision and hearing 
impairment, and cerebral palsy, and conducts surveillance and 
epidemiology studies of human exposure to lead, radiation, air 
pollution, and other toxicants. A major focus of the NCEH 
Strategic Plan is the incorporation of advances in genetics into 
its research, epidemiology studies, and disease prevention 
programs (CDC 2000a). NCEH has a laboratory with expertise 
in analyzing biological samples for environmental 
contaminants, which is developing improved analytical methods 
for blood and urine samples from children (CDC 2000b). 

CDC’s National Center for Health Statistics (NCHS) 
is conducting the fourth National Health and Nutrition 
Examination Survey (NHANES IV), a national survey of health 
and nutrition. NHANES IV will have about 30,000 respondents 
and will include sufficient numbers of children in selected age 
ranges to allow statistical inferences about their health, 
nutrition, and food intake, and the concentrations of some 
environmental contaminants in their blood and urine. ORD is 
collaborating with NCHS to collect information on children’s 
exposure to pesticides and other environmental contaminants. 
NHANES has been conducted since 1971, and data from 
NHANES III are now available (CDC 2000c). 


NCI conducts population-based research on 
environmental and genetic causes of cancer and on the role of 
biological, chemical, and physical agents in the initiation, 
promotion, and inhibition of cancer. NCI’s Agricultural Health 
Study (AHS) is a large epidemiology study of cancer in farm 
workers and their families. ORD is participating in the AHS 
through an exposure study of a subgroup of participants. NCI 
also supports human-subject research aimed at understanding 
the molecular causes of specific cancers in children and the 
reasons for treatment failure. The pediatric Clinical Trials 
Cooperative Groups (Children's Cancer Group, Pediatric 
Oncology Group, National Wilms' Tumor Study Group, and 
Intergroup Rhabdomyosarcoma Study Group) develop 
research protocols used in the treatment of the majority of 
children with cancer in the United States and represent a 
significant portion of the U S. clinical research on childhood 
cancers. A significant portion of children with cancer in the 
United States are enrolled in Federal programs. NCI also 
supports grants including laboratory and epidemiological 
studies of pediatric cancer survivors. To date, these studies 
have not focused on possible environmental causes of 
childhood cancer (NCI 2000). 

NIEHS is conducting a study in Norway investigating 
the hypothesis that the interaction between environmental 
agents and genetic polymorphisms makes the fetus more 
susceptible to cleft palate. For this study, both genetic samples 
and data on environmental exposure of mothers and infants 
are being collected (NIEHS 2000c). 

The National Survey of Lead and Allergens in Housing 
is a joint effort of the Department of Housing and Urban 
Development (HUD) and NIEHS. HUD is studying the 
prevalence of lead-based paint, lead in house dust, and lead in 
soil (HUD 2000). NIEHS is studying the prevalence of 
allergy-inducing materials in house dust. This study involves 
visits to more than 8,000 homes from 75 areas selected to 
reflect the national housing stock, collection of environmental 
samples, and interviewing of occupants (NIEHS 2000d, e). 

4.2.4. Exposure-Dose-Response Modeling 
and Risk Assessment 

The number and types of direct exposure 
measurement studies are limited by their relatively high cost 
and the difficulties in studying children. Another type of 
exposure study design uses a mathematical model to combine 
spatial and temporal information on pollutant concentrations 
with population distributions of time-activity and location data 
and other exposure-related data to estimate exposure. 
Variables in the models are evaluated using existing data from 
many sources. ORD is using the results of data from 
completed and ongoing studies to develop age-specific 
exposure models. ORD also sponsors research to understand 
and quantify factors, such as intake and contact rates and 
durations and frequencies of exposures, that contribute to 
estimates of total exposure. Children’s exposures to pesticides 


14 



via the dermal route, through nondietary ingestion of pesticides 
on surfaces and in soil and dust, and through contact with 
pesticide-treated pets are being studied. Transport of 
pesticides from outdoors to indoors and movement and 
persistence in the indoor environment are also being studied. 
Existing data are being analyzed to determine children's 
activities and dietary and nondietary exposures. Measurement 
protocols and models are being developed to account for 
exposures that occur when children eat food they have placed 
on floors recently treated with pesticides. 

Exposure-to-dose models are being developed for 
estimating concentrations of contaminants in biological media 
(blood and urine) and doses of contaminants to target organs. 
These models take into account age-related differences in 
absorption, metabolism, distribution, and elimination and 
differences in the structure, composition, and function of 
organs and systems. ORD, OPPTS, and the Office of 
Emergency and Remedial Response (Superfund) developed 
the Integrated Exposure Uptake Biokinetic (IEUBK) model 
(EPA 1995b), which estimates children’s blood lead levels from 
environmental concentrations of lead, taking into account 
physiologic characteristics of a small child. The IEUBK model 
is used to assess risk at Superfund sites and was used in an 
EPA risk assessment to determine lead cleanup levels in 
residences (EPA1998f). Work is ongoing to develop a 
modeling framework and an integrated group of models that 
can be easily modified for a variety of environmental agents 
and exposure scenarios for children. The modelswill describe 
transport in microenvironments and contact with and uptake 
into the body by multiple routes of entry. Another research 
effort is focused on collecting child-specific data on lung 
structure and respiration and incorporating it into dose- 
response methods for estimating exposures and risks from 
inhalation of contaminants. This project will be expanded to 
include the ingestion and dermal routes. 

Long-term research is being conducted to design a 
BBDR model for developmental toxicity. Thus far, research 
has focused on prenatal development and chemicals for which 
metabolic pathways, cellular mechanisms of action, and toxicity 
profiles are known. In the shorter term, ORD is working on 
BBDR models that will incorporate differences in carcinogenic 
effects resulting from childhood and adult exposures to permit 
estimation of cancer risk from partial lifetime exposure of any 
given duration beginning at any given age. 

EPA develops and distributes risk assessment 
information through the Integrated Risk Information System 
(IRIS), including oral RfDs and inhalation RfCs for chronic 
noncarcinogenic health effects and slope factors or unit risks 
for carcinogenic effects (EPA 2000d). Information on children 
is included in IRIS where data are available. ORD guidance 
documents such as the Exposure Factors Handbook (EPA 
1997d) provide analyses of existing data on children and 
recommendations for evaluation of exposure variables for use 
in risk assessments. A companion project examines the 


differences in exposure to environmental contaminants in 
children by racial, ethnic, and socioeconomic groups. ORD 
supports the Developmental and Reproductive Toxicology 
(DART) Database in collaboration with the National Institutes 
of Health (NIH) and FDA. DART is an online bibliographic 
database containing about 80,000 references. Ongoing 
maintenance by the National Library of Medicine includes 
adding 3,500 to 4,000 references per year and improving the 
search capability. 

4.2.5. Risk Management and Risk 
Communication 

A basic tenet of risk management is that public health 
problems resulting from exposures to environmental 
contaminants can be more efficiently corrected by preventing 
the exposures than by administering medical treatment after 
the effects occur. The U.S. Government’s most highly visible 
action relating to children’s health is the control of lead 
exposure through removal of lead from gasoline and paint and 
the accompanying rapid reduction in blood concentrations of 
lead in the nation's children. 

One way to reduce risk is by using engineering 
controls and treatment and cleanup methods to reduce the 
amount of a substance released to the environment. Currently, 
ORD is developing new technologies to control emissions that 
disproportionately affect children. This research includes 
development of drinking water treatment technologies that 
reduce Cryptosporidium oocysts in water, indoor air treatment 
procedures that remove fine particulates, and development of 
efficient and cost-effective particulate controls for large 
industrial combustors and incinerators. 

Controls at the source often require disposal of 
pollutants and may simply transfer the problem from one 
environmental medium to another. Pollution prevention avoids 
this problem by reducing the amount of contaminant available 
for release to the environment through increased efficiency in 
the use of raw materials, energy, water, or other resources 
(EPA 1998g). ORD is developing processes and products that 
will generate or release lower levels of substances that have a 
disproportionate impact on children. Pollution prevention 
research projects aimed at reducing exposure to particulate 
matter include development of better consumer products to 
mitigate indoor air problems originating from indoor sources, 
development of better construction techniques to reduce the 
infiltration of outdoor pollutants to the indoor environment, 
studies on emissions from several types of oil and coal under 
differing combustion conditions and with different pollutant 
controls, testing of emissions from new and older designs for 
diesel engines, and improved choice of materials and design of 
automobile and truck tires to reduce creation of fine particulate 
during use. 

EPA is exploring ways to address children’s 
environmental health risks through partnerships with 


15 



communities. NIEHS requires that all of its centers develop 
and maintain community outreach and participation programs. 
All of the EPA/NIEHS Centers for Children’s Environmental 
Health and Disease Prevention have projects in which the 
grantees work closely with parents and other members of the 
community to mitigate unacceptably high exposures to 
environmental contaminants. In another ORD study, the 
impact of improved community drinking water supplies is being 
evaluated by assessing the occurrence of microbial enteric 
disease in children 2 to 10 years old before and after changes 
in drinking water supplies or treatments are implemented. 
ORD is investigating pesticide poisoning reports in children six 
years and younger in the Lower Rio Grande Valley to 
determine whether they are at increased risk of pesticide 
poisoning, identify risk factors, and develop intervention and 
prevention strategies. 

EPA’s Regional Offices are working with communities 
to address environmental health threats to children. For 
example, Region 5 is conducting intervention studies on 
childhood asthma in Milwaukee and working to improve indoor 
air quality in Chicago schools. Regions 2 and 7 are planning 
to develop an instructional video for urban poor populations 
recommending techniques for controlling asthma by reduction 
of children’s exposure to cockroach and dust mite allergen, 
pesticides, molds, pet dander, and secondhand smoke. The 
Chippawa Cree Tribe and Region 8 have entered into a 
cooperative agreement to identify and reduce environmental 
health threats to the Tribe's children in north-central Montana, 
initially focusing on lead hazards, unsafe drinking water, and 
second hand smoke. The Office of Air and Radiation (OAR) 
has developed and implemented the EPA SunWise School 
program to mitigate children’s health risks related to 
overexposure to ultraviolet radiation. Descriptions of more 
EPA community-based projects can be found in the CHEHSIR 
database (EPA 2000b). 

The Agency for Toxic Substances and Disease 
Registry (ATSDR), created to deal with hazardous waste 
issues, has a major role in communicating and working with 
individuals and communities. ATSDR advises community 
members and others of the health impacts of Superfund sites, 
identifies communities where people might be exposed to 
hazardous substances, conducts health studies in 
communities, determines hazards, and recommends actions to 
safeguard health (ATSDR 2000). 

4.3. Research Areas and Priorities 

A strategy for research in children’s risk must be 
broad enough to address diverse environmental contaminants, 
endpoints, and special groups such as farm children and urban 
children. The relative importance of research areas may shift 
rapidly as more becomes known about the impact of 
environmental contaminants on children’s health and new 
methods become available to study the gene-environment 
interactions that lead to adverse effects. The science team 


decided that a research strategy directed at specific 
environmental problems and endpoints would not provide 
sufficient flexibility and might impede the development of new 
approaches to risk assessment. Issues surrounding children’s 
environmental health are too numerous to address individually 
in this strategy, and current knowledge is limited, making it 
difficult to foresee emerging issues and future directions. Other 
EPA groups are developing research recommendations for 
addressing children's environmental health, including the U.S. 
Task Force, the EPA 10X Task Force, the Office of Children’s 
Health Protection, and ORD programs under GPRA goals 1 
through 5 (Clean Air, Clean Safe Water, Safe Food, Safe 
Communities, and Safe Waste Management). The strategy is 
organized into 5 main topic areas encompassing 13 research 
areas that cut across all environmental problems and address 
the research questions presented in Section 1: 

■ Development of data for risk assessment 

Mode-of-action research 

Epidemiology studies 

Exposure field studies 

Activity pattern and exposure factor studies 

■ Development of risk assessment methods and 
models 

Methods and models for using mode-of-action 
data in risk assessments 
Methods and models for using exposure data 
in risk assessment 

■ Experimental methods development 

Methods for hazard identification 
- Methods for measuring exposures and effects 
in children and to aid in extrapolations 
between animals and humans 

■ Risk management and risk communication 

Multimedia control technologies 
Reduction of exposure buildup of 
contaminants indoors 

Education and communication of risk and risk 
reduction techniques 

■ Cross-cutting issues 

Variation in human susceptibility and exposure 
Mixtures/cumulative risk 

Appendix E contains a cross tabulation showing relationships 
between the research areas and the research questions. 

After developing the research areas, the science team 
considered how the research might be conducted. ORD has 
intramural and extramural research programs. The intramural 
program is organized into three national laboratories and a 
national center: NHEERL, the National Exposure Research 
Laboratory (NERL), the National Risk Management Research 
Laboratory (NRMRL), and the National Center for 


16 



Environmental Assessment (NCEA). The extramural Science 
to Achieve Results (STAR) program is administered by the 
National Center for Environmental Research (NCER). The 
science team considered the following possibilities for 
conducting research: 

■ ORD scientists as principal investigators, often in 
collaboration with scientists in government, academia, 
and private firms through interagency agreements, 
cooperative agreements, and contracts (the 
intramural program); 

■ academic scientists as principal investigators under 
grants funded through the STAR program; and 

■ scientists supported by other Federal agencies 
without active ORD collaboration or support. 

Priorities were determined for both the intramural and 
the STAR programs. In setting priorities, the science team first 
considered using the criteria set out in the ORD Strategic Plan 
(EPA 1997c). The ORD criteria were found to be specific to 
particular health effects, methods or models for assessing risk, 
or risk management techniques. They are problem-specific 
and difficult to apply to research areas that are more broadly 
defined. Therefore, the science team developed and used the 
following criteria to rank the topic areas: 

■ importance of the research to reducing uncertainty in 
risk assessment and protecting children from 
environmental health threats; 

■ feasibility of conducting the research in the ORD 
intramural or STAR programs; 

■ availability of resources, including the capacities and 
capabilities of ORD’s laboratories and centers and the 
extramural resources; 

■ opportunities to develop and maintain scientific 
expertise in ORD to enable use of research results in 
EPA risk assessment; 

■ opportunities for collaboration with other Federal 
agencies and with other ORD research programs; 
and 

■ maintenance of a balance between short-term 
research that will reduce major uncertainties in risk 
assessment and long-term, more speculative 
research that may identify hazards and exposures to 
children or change EPA’s way of doing risk 
assessments and ultimately produce more accurate 
and less costly assessment procedures. 

This section describes each research area and 
discusses the feasibility of conducting the research in ORD. 


Each research area is rated as high, medium, or low; and a 
rationale is provided for the rating. For the high-priority areas, 
long-term outcomes and short-term outputs for the next 5 years 
are also provided. Appendix F shows the application of the 
criteria to each research area. 

4.3.1. Laboratory Studies and Surveys 

This section describes the laboratory and field 
research that will provide the database to identify and assess 
environmental health threats to children. It includes human, 
animal, and in vitro studies, and studies of sources, pathways, 
and other factors influencing exposure. 

4.3.1.1. Biology of Toxicant-Induced Tissue and Organ 

Damage in the Developing Organism 

Description. Sound biological data are needed to 
facilitate the interpretation and extrapolation of animal and 
human data for risk assessment. Even though certain agents 
have been identified as causing developmental abnormalities, 
current understanding of the pharmacokinetics and modes of 
action underlying these alterations is minimal. In this research 
area, data will be developed to link environmental exposures 
and doses with biologically effective doses at the cellular and 
molecular levels. 

Data on absorption, metabolic pathways and rates, 
distribution and storage in the body, and elimination will be 
developed for sensitive age groups. Hypothesis-based studies 
will be conducted to study modes of action with the goal of 
linking developmental effects at the tissue, organ, and system 
levels with the underlying effects at the cellular and molecular 
levels. Investigation of modes of action may include, for 
example, examination of disturbances resulting from alterations 
in metabolism, DNA repair, cell viability, and receptor-mediated 
alterations in gene expression. The biologic bases for age- 
related differences in target organ development, detoxification, 
repair, and compensation will be investigated using in vivo and 
in vitro experimental models. At a minimum, studies will be 
conducted during the period of development that is the most 
sensitive to perturbation by the toxicant in question. Data are 
also needed to determine if the pharmacokinetics and modes 
of action of a toxicant are similar across different age groups 
and across different species. The ideal study would include 
more than one age group so that an overall model at various 
developmental stages could be produced. 

A critical review of studies of prescription drugs to 
elucidate what mechanisms of action might be expected to 
produce the greatest age-related susceptibilities might be a 
useful exercise to help design studies of environmental 
contaminants. A first exercise might be to explore whether 
appropriate models have been developed for organ systems of 
concern and how well existing models match up across organ 
systems. 


17 



Feasibility. ORD has the expertise to study the 
pharmacokinetics and modes of action that result in adverse 
effects in children. As discussed in Section 4.2.2, ORD 
supports ongoing research in this area in both the intramural 
and the STAR program. The current effort directed at 
children’s issues needs to be expanded, however, particularly 
in the intramural program. NIEHS also supports research 
aimed at identifying the underlying modes of action by which 
toxicants affect biological systems, and it is important to 
continue collaborations and make full use of results from the 
NIEHS program. 

Priority and Rationale. High. These studies and the 
methods and models described under Sections 4.3.2.1 and 
4.3.3.1 are critical to increasing the use of biological data in 
children’s risk assessments, particularly in selecting 
appropriate animal models and endpoints and for improving 
extrapolations from animals to children. Current approaches 
in risk assessment rely on assumptions that in many cases 
have only limited explanations based on biology. These 
include assumptions that are made in extrapolating (or 
interpolating) from laboratory animals to humans, from high to 
low exposure levels, over various exposure durations, and over 
changing critical periods of susceptibility, especially in the case 
of the developing child. Biologically based dose-response 
models should lead to refined risk assessment approaches that 
no longer rely solely on whole-animal toxicity testing, but 
incorporate the growing knowledge of molecular mechanisms 
and their involvement in a toxic response. It should be 
possible to develop testing paradigms using in vivo and in vitro 
approaches that are more biologically based and that address 
such issues as complex mixtures, varying exposure patterns, 
and critical periods of susceptibility. This research can be 
conducted in both the STAR and intramural programs and will 
require a long-term commitment of resources. It is essential to 
maintain and expand ORD capability through a strong 
intramural program to support the focused research necessary 
to improve EPA assessments. 

Long-Term Outcomes. Mechanism-of-action 
experimentation facilitates the extrapolation of animal and 
experimental model data to humans, enhancing ability to 
predict and study adverse effects in humans. Mode of action 
becomes an integral component of risk assessment. Advances 
in genomics/proteomics are incorporated into EPA’s risk 
assessment methodologies. 

Short-Term Outputs. ORD will 

■ Develop better quantitative characterizations of dose 
to target tissue in developing organisms to replace 
default assumptions in children’s risk assessments. 

■ Link developmental effects at the tissue, organ, and 
system levels with the underlying effects at the 
cellular and molecular levels to develop first- 
generation biologically based predictive models. 


■ Develop and validate sensitive and predictive 
methods using laboratory animals to determine mode 
of action by linking developmental effects at the 
tissue, organ, and system levels with the underlying 
effects at the cellular and molecular levels. 

■ Validate in vitro assays (using either animal or human 
biological material) for inclusion in the overall risk 
assessment process. 

4.3.1.2. Relationship Between Exposure to Environmental 
Agents and Adverse Health Effects in Human 
Populations 

Description. Well-designed epidemiological and 
clinical studies are needed to evaluate associations between 
prenatal and postnatal toxicant exposure and altered 
development, maturation of organs and systems, and 
developmental disorders such as childhood cancer, asthma, 
neurotoxic effects, reproductive effects, and birth defects. 
These studies will improve our ability to identify, characterize, 
and quantify toxicant-induced alterations in the structure and 
function of organs and systems during growth and 
development. A variety of criteria could be used to identify 
candidate populations. These criteria would include, but would 
not be limited to, inadvertent or accidental exposure to a known 
toxicant, exposure of a number of different age groups, the 
likelihood of obtaining useful dosimetric information (i.e., the 
ability to obtain data useful for quantifying age-specific external 
and internal dose), and availability of sensitive and predictive 
test methods for the target organ or system of concern. 

One such study is a case-control study of a group of 
children with health effects that are known or suspected to be 
related to exposure to environmental pollutants. Based on the 
existing human and animal database for neurotoxicity of lead, 
certain pesticides, and PCBs, individuals with neurological 
diseases would be an appropriate group for such studies. 
Retrospective data on cases and controls could be collected 
through questionnaires, and both biological and environmental 
samples might be appropriate. It would be advantageous if 
subjects could also be monitored through early adulthood to 
test for persistent and latent effects. 

Alternatively, prospective studies of childhood 
exposures to environmental contaminants and their associated 
effects in juvenile populations could be undertaken. A 
longitudinal study, similar to the 50-year-old Framingham Heart 
Study, sponsored by the National Heart, Lung, and Blood 
Institute, has been recommended by some experts to attempt 
to clarify the connection between childhood exposures to 
environmental agents and adverse health effects in childhood 
or adulthood (NHLBI2000). In such a study, individuals would 
be enrolled at an early age, perhaps at birth, and followed into 
adulthood. Data on health and nutrition would be collected, as 
well as exposure data. 


18 




Feasibility. Human studies of the cause-effect and 
dose-response relationships between environmental 
contaminants and adverse health endpoints are most feasible 
for ambient contaminants, such as air and drinking water 
pollutants, and for easily observed effects associated with a 
single route and pathway of exposure, such as respiratory 
distress and enteric disease. The ORD intramural and STAR 
programs have experience in conducting human studies. Many 
of the current ORD-supported human studies of children 
involve respiratory endpoints. The impact of pesticide 
exposure on children, which can occur by multiple routes and 
have more than one source, is an expanding research area 
(see the discussion of EPA 1998b, in Appendix C). As 
discussed in Section 4.2.3, the STAR program is funding eight 
centers, each of which includes an epidemiology/intervention 
study. 

One of the problems in conducting epidemiology 
studies of environmental agents is obtaining an accurate 
estimate of exposure levels over time. ORD, with a research 
laboratory (NERL) devoted to exposure science, is well 
positioned to address this issue. For example, as discussed in 
Section 4.2.3, NERL and NHEERL are collaborating in an 
exposure and epidemiology study of health effects in children 
along the U.S.-Mexico border. 

ORD is collaborating with other Federal agencies in 
pilot studies to investigate the feasibility of a longitudinal birth 
cohort study under the auspices of the Developmental 
Disorders Working Group of the U.S. Task Force. The 
proposed study would enroll as many as 100,000 mothers 
during pregnancy and follow the children over time. EPA, 
NICHD, and CDC are the lead agencies in this effort. 

A longitudinal study is expensive and would require a 
long-term commitment of resources and partnerships with other 
agencies. Relationships between exposure to environmental 
agents and adverse health effects are usually difficult to 
observe. If only a small percentage of the population 
experiences an effect, a large sample size is a prerequisite for 
testing hypotheses related to environmental exposures. 
Exposure levels are often difficult to quantify and other possible 
causes of the adverse effect are usually present. 

More focused epidemiological and clinical studies will 
have varying costs and chances for successful outcome. 
Studies conducted in human populations should be carefully 
designed to ensure the maximum potential for identifying 
hazards and developing dose-response relationships. 
Collection of exposure data adequate to develop dose- 
response relationships is essential. One less costly and 
potentially effective study would be to test hypotheses using 
existing databases such as NHANES. 


to environmental contaminants than are adults. The results of 
current Federal research into the causes of childhood asthma 
and the effects of exposure to organophosphates and PCBs, 
for example, may provide ORD with insights to guide the 
design of future studies of children. 

Hypothesis-based human epidemiologic and clinical 
studies are necessary to confirm that adverse effects occur in 
humans, to improve extrapolations from animal data to 
humans, and to develop data to incorporate into risk 
assessments. Human studies should be conducted as needed 
for high-priority environmental agents and to assist in model 
development and validation. It is expected that human studies 
will be supported for particular high-priority agents and 
populations under program-specific research, as well as under 
the STAR program. Factors that improve the probability of 
observation of cause-effect and dose-response relationships, 
such as existence of sensitive biomarkers of effect, would also 
raise the priority of a human study. The strategy for the 
intramural Children’s Health program is to focus on mode-of- 
action research and modeling and to incorporate clinical and 
epidemiology studies as necessary to reach this primary goal. 
Such studies should be hypothesis based and the biological 
basis for conducting the study should be clearly defined. 

As discussed in Section 4.2.3, several Federal 
agencies in addition to EPA, including CDC, NCI, NIAID, and 
NIEHS, support epidemiologic and surveillance programs. A 
major objective of some of these studies (e g., the Inner-City 
Asthma Study) is to identify relationships between exposures 
to environmental contaminants and adverse effects in children. 
Other studies, such as the CDC surveillance and epidemiology 
studies of developmental disorders in children in Atlanta, have 
not yet focused on environmental agents as risk factors. 
Through the Developmental Disorders Working Group of the 
President’s Task Force on Children’s Environmental Health 
and Safety, EPA, CDC, and several of the Institutes of NIH are 
exploring the feasibility of an interagency longitudinal birth 
cohort study to address children’s environmental health and 
safety issues. The study would have a core protocol that would 
be followed for each member of the cohort and special studies 
that would allow for collection of additional data addressing 
specific issues of participating agencies. It is recommended 
that ORD continue with this process and explore 
implementation through the STAR program or through a 
proposal for an Initiative in FY2003. 

Long-Term Outcome. Environmental agents and 
other factors contributing to adverse effects in children are 
identified, status and trends in children’s health and exposure 
to environmental agents are characterized, and risk reduction 
methods are successfully implemented. 

Short-Term Outputs. By 2005, ORD will 


Priority and Rationale. High. Human studies are 
crucial to understanding whether children are more susceptible 


19 


Analyze relationships between childhood exposures 
to air pollutants and respiratory effects under the 




STAR program. 

■ Analyze relationships between childhood exposures 
to pesticides and neurological effects under STAR 
program. 

■ Develop, refine, and pilot methods for conducting a 
hypothesis-based longitudinal study of developmental 
disorders in a large birth cohort under the U.S. Task 
Force on Children’s Environmental Health and Safety. 

4.3.1.3. Multimedia, Multipathway Exposures in Human 
Populations 

Description. Exposure studies are closely related to 
the epidemiological studies described in the preceding section. 
Epidemiology studies examine the link between exposure and 
disease. Exposure studies quantify exposure levels, 
investigate the reasons for exposure, identify sources of 
exposure, and provide information needed to devise strategies 
to reduce the risk. Ideally, epidemiological and exposure 
studies are combined. However, as the number of issues 
being studied increases, the number of measurements taken, 
questions asked, and time required can become intolerable to 
respondents, who will refuse to participate or drop out of the 
study. Consequently, human studies are carefully designed to 
limit respondent burden to an acceptable level and sometimes 
address only the exposure questions. 

In a typical exposure study, samples of the child's 
environment (e.g., air, soil, dust), biological samples (e g., 
blood, urine, feces, breath, hair), and personal exposure 
samples (e.g., personal air samples taken by a collection 
device worn by the child, samples of food and drinking water) 
are collected, as well as questionnaire data on activities, 
sources of exposure, and sometimes health status. Analysis 
is performed on the samples for suites of chemicals in one or 
more chemical classes. 

Some current studies target the national population, 
but more typically, exposure studies focus on subgroups 
hypothesized to be highly exposed or on a city or region. 
National studies tend to have larger numbers of people in the 
sample, but to collect fewer samples per individual. The 
NHANES-IV study of children’s exposure to pesticides, for 
example, will provide a urinalysis and responses to a few 
questions about pesticide exposure for about 1,800 subjects. 
More targeted studies collect and analyze samples from many 
media on fewer subjects. In NHEXAS, EPA sponsored studies 
of the general population and special subgroups in regional and 
local areas, including a six-State study in the Midwestern Great 
Lakes Region with a special study of children in Minnesota, a 
State-wide study in Arizona with a special study of people living 
along the U.S.-Mexico border, and a five-county study in and 
around Baltimore to test temporal variability in exposure. 
These studies asked more than 300 questions and collected 
thousands of samples on approximately 60 to 300 respondents 


per study. 

Some critical questions can best be answered through 
probability-based exposure studies: What are children 
exposed to? Are particular age group, such as toddlers, more 
highly exposed? If so, what are the most important 
contaminants and exposure pathways for these age groups? 
What are the most highly exposed groups of children (e.g., 
farm children, inner-city children)? Does exposure vary with 
climate and region? How does exposure vary over time? 

Feasibility. ORD has extensive experience in both 
the intramural and STAR programs in conducting and 
supporting exposure studies. 

Priority and Rationale. High. It has been repeatedly 
hypothesized that children are more highly exposed to 
chemicals in the environment than are adults and that some 
age groups, such as toddlers may be more highly exposed 
than other children. However, data to test these hypotheses 
are limited. Probability-based exposure studies, where 
respondents are randomly selected to represent the study 
population, can be used to: 

■ document exposures and determine whether certain 
age groups are more highly exposed to certain 
environmental agents; 

■ provide baseline data on children’s exposures by age 
to determine national exposure levels, evaluate status 
and trends, and identify and characterize highly 
exposed subgroups; 

■ assess exposure and risk for specific populations of 
children; 

■ assess total exposure to multiple chemicals via 
multiple pathways and determine the relative 
importance of the sources contributing to the 
exposure; 

■ develop models to estimate multimedia, multipathway 
exposures; and 

■ evaluate exposure variables in models, such as 
children’s activity patterns. 

Some exposure questions may be answered for 
specific chemicals through an analysis of existing data or data 
that will soon be available from NHEXAS, NHANES, and the 
STAR grants. As the questions are answered for specific 
chemicals, the information can be generalized to other 
chemicals to which children might be exposed by the same 
pathways, reducing uncertainty for entire classes of chemicals. 

Exposure studies should be directed toward 
chemicals of high concern because of their known or 


20 




suspected hazards. In designing studies, investigators should 
consider the research questions of interest, the various types 
of information (health, exposure, source) that could be 
collected, and the uses of that information in risk assessment 
and risk management before deciding whether health data 
should be collected or whether health data should be foregone 
in favor of more data on sources, exposures, and exposure 
factors. 

Because of the high cost of exposure studies, ORD 
should explore partnerships with other Federal agencies and 
the possibility of conducting some of this work under other 
ORD research programs such as the Safe Food program and 
Human Health Risk Assessment program. 

Long-Term Outcomes. Status and trends in 
children’s exposures to environmental agents are characterized 
using baseline data developed in this program. Highly exposed 
subpopulations of children are identified, important sources and 
pathways of children’s exposures are delineated, and risk 
management interventions are successfully implemented. 

Short-Term Outputs. By 2005, ORD will 

■ Conduct analysis of existing data from NHEXAS, 
NHANES, and STAR grants to provide answers to the 
extent possible on whether children are more highly 
exposed, which age groups are more highly exposed, 
and important sources and pathways. 

■ Develop new sampling protocols, questionnaires, and 
study designs based on previous studies of children’s 
exposure. 

■ Design and initiate field studies to answer questions 
about children’s exposure, with Federal partners 
where feasible. 

4.3.1.4. Analysis of Factors Contributing to Exposure 

Description. Exposure models allow risk assessors 
to generalize from existing data and estimate exposures to 
subpopulations and environmental agents for which data are 
not available. This capability is crucial to EPA's regulatory 
programs, where thousands of assessments are performed 
yearly, often for subgroups, locations, and environmental 
agents for which there are few data. Questionnaire-based 
surveys and laboratory studies are used to develop data for 
evaluation of exposure variables used in risk assessments. 

For key exposure variables and factors, exposure 
measurement studies help to characterize distributions of 
values by age groups in the U.S. population and in important 
subgroups. Key variables include duration and frequency of 
exposure, dietary intakes, physiologic parameters, and many 
others. Some pathways of interest for children are exposure 
through pollutants on floors, in household dust, and in the small 


child’s indoor breathing zone through inhalation, ingestion, and 
dermal contact; exposure to pollutants in soil (inadvertent 
ingestion, pica, inhalation while playing sports); exposure away 
from the home; and exposure to pollutants in water and 
sediment during swimming and wading through dermal contact 
and ingestion. It is especially important to determine how, 
when, and for how long children come in contact with media 
that have higher concentrations of toxic chemicals. For 
example, aoes baby food have more contaminants than a 
frozen dinner? How does the breathing zone for indoor air in 
a day care center compare to that in a typical residence? How 
often do children touch contaminated surfaces and lick or suck 
on their fingers, toys, and other objects? What is the 
distribution of ingestion rates of soil and dust among children 
in various age ranges? What are typical transfer rates of soil, 
dust, and pollutants from hand to mouth and what factors 
determine transfer rates? 

Feasibility. It is feasible to conduct some of these 
studies under the STAR program. For example an investigator 
working under an EPA grant, is treating dogs with pesticides 
and measuring the dislodgeable residue over a period of time 
to address transfer of pesticides in flea treatments from pets to 
children. It is feasible to design and conduct studies to collect 
data on children’s activities that parents and caretakers can 
easily observe. Some types of activities, however, such as 
ingestion of dust and soil by young children or trespassing by 
older children on waste sites are very difficult to document. 
Studies to collect data on dermal exposure and nondietary 
ingestion are difficult to design because of lack of validated 
measurement methods and models for these pathways. 

Priority and Rationale. High. EPA needs data that 
can be used to improve risk assessments for children in the 
short term. Data on one or two key factors could have a 
substantial impact on reducing uncertainty in hundreds of 
assessments as well as in helping to design future studies. 
The variables need to be selected to maximize the reduction of 
uncertainty. For example, by studying the exposure pathways 
that are common to many chemicals and are highly applicable 
to children’s activities, uncertainties could be reduced for a 
number of assessments through a single study. This approach 
could have a higher information return on investment than a 
detailed study of all pathways for one chemical. Some studies 
will need to be conducted within the ORD intramural program 
to obtain data for EPA risk assessments. Others could be 
conducted underthe STAR program and under media-specific 
ORD programs. For example, FQPA resources could be used 
to study important exposure variables in the OPP Standard 
Operating Procedures (Versar 1997). 

Long-Term Outcomes. Residential exposure factors 
for children will be characterized by age and sex for the 
national population, regional populations, highly exposed 
groups, and susceptible groups. Factors include activity 
patterns (time spent in a given activity and frequency of 
occurrence), soil and dust ingestion rates, factors reflecting 


21 




transfer of environmental agents from objects and surfaces 
children commonly touch, and factors related to ingestion of 
chemical residues on surfaces. 

Short-Term Outputs. By 2005, ORD will 

■ Identify high-priority exposure variables for study 
through preliminary exposure analysis. 

■ Design and complete an activity pattern survey 
addressing high priority activity pattern issues for 
children. 

■ Complete two studies on other high-priority exposure 
variables for children. 

4.3.2. Risk Assessment Methods and 
Models 

In order to make full use of research in risk 
assessments, EPA needs methods and models that will help 
generalize the results. This section discusses development of 
methods and models for using biological and exposure data in 
risk assessments for children. 

4.3.2.1. Methods and Models for Using Biological Data in 
Risk Assessment 

Description. Although there is a considerable 
amount of research directed at the biology of normal and 
abnormal development, these data have not been fully used in 
EPA assessments, in part because agreed-upon biological 
assessment methods do not exist. This research area is aimed 
at developing methods and models for routine use of biological 
data in risk assessment. A major focus is to develop models 
linking developmental effects at the tissue, organ, and system 
levels with the underlying interactions at the cellular and 
molecular levels. A second focus is to link PBPK and BBDR 
models to provide an integrated biological model of the 
exposure-dose-response continuum for children. Additional 
focus is on improving extrapolations of laboratory data to the 
human condition. The research area will consist of both short¬ 
term research to improve existing methods and models and 
long-term research to develop better, biologically based models 
that are able to make use of pharmacokinetic and mode-of- 
action data to relate exposures and effects. There is a need to 
develop exposure-dose-response models for vulnerable ages 
from conception through adolescence that reflect the effects of 
toxicant exposure during early development. This research 
area is closely related to the development of biological data for 
risk assessment (Sections 4.3.1.1 and 4.3.3.1). Existing 
biological data and the results of the laboratory program will 
provide the basis for the development of biological methods 
and models. As the assessment methods evolve, hypotheses 
will be generated and data gaps highlighted to help design 
future laboratory studies. 


Feasibility. Although some prototype models could 
be developed through the STAR program, the greater part of 
this research will need to be done intramurally so that ORD has 
the ability to direct the research toward EPA’s risk assessment 
needs. The resources required to address the above issues 
will be extensive. A suggested approach is to begin expanding 
ORD’s capabilities in several critical areas (developmental 
toxicology, neurotoxicology, immunotoxicology, respiratory 
toxicology) with the specific aim of building from the 
considerable expertise that EPA has developed in these areas. 
Realistic financial and scientific resources should be made 
available, based on how current efforts in the critical areas can 
be expanded to the periods of child development of interest. 
These efforts should be coordinated with ORD’s STAR 
program. The science team noted that a critical mass of 
scientists dedicated to this research area and maintained 
consistently over a long-term period is necessary to make 
progress in this area. An accompanying program of laboratory 
experiments as described above in Sections 4.3.1.1 and 
4.3.3.1 must also be maintained. 

Priority and Rationale. High. The rationale is 
presented in Section 4.3.1.1. 

Long-Term Outcome. Broadly applicable PBPK and 
BBDR models will be routinely used to produce more accurate 
risk assessments for children, making full use of 
pharmacokinetic and mode-of-action data. 

Short-Term Outputs. By 2005, ORD will 

■ Evaluate the appropriateness of the assumptions in 
current EPA risk assessment approaches and how 
they may be supported or modified by biological data. 

■ Develop and refine PBPK models applied to the 
developing animal, with the intent of eventual 
extrapolation to embryos, fetuses, infants, and 
children. 

■ Develop and refine BBDR models applied to the 
developing animal with the intent of extrapolation to 
embryos, fetuses, infants and children. 

■ Identify biological pathways, environmental factors, 
and their interactions that are important to 
understanding normal and abnormal development 
with a focus on incorporation of such information into 
predictive models of developmental toxicology and 
not solely on the generation of basic information on 
child development. 

■ Define how experimental animal models mirror child 
development and develop appropriate correction 
factors for species differences. 

■ Incorporate information from dose-response, 


22 




pharmacokinetic, and mode-of-action studies in 
animals into models that more accurately predict 
children’s risks. 

■ Develop first-generation methods, guidance, and data 

for broad application of modes of action and 
pharmacokinetics in EPA risk assessments for 
children. 

4.3.2.2. Exposure Modeling and Use of Exposure Data in 
Risk Assessment 

Description. Exposure models are needed when it 
is not possible to measure exposure directly, either because 
there is currently no way to make the measurement (e g., 
concentration in target organs) or the measurement is too 
costly or too burdensome on the study subjects. Most 
exposure assessments for children at EPA rely on models 
rather than direct measurements of exposure. 

Exposure models are used in research to help 
understand the relationships between exposure variables and 
to generate hypotheses to be tested in the field or the 
laboratory. They are used in risk assessments to identify and 
quantify risks that may require risk management actions. And 
they are used to identify sources of exposure for the purpose 
of developing and evaluating risk management options and 
regulations that reduce risk through approaches such as 
testing for adverse effects, limiting releases to the environment, 
and banning chemicals from commerce. 

Models will be developed to assess pathways of 
exposure important to children. Models capable of estimating 
total absorbed dose via multiple pathways and predicting 
variability of individual exposures in a population whose 
members are simultaneously exposed to multiple chemicals via 
multiple pathways are needed to estimate children’s exposure. 
Models need to be capable of performing probabilistic analysis 
and taking into account correlations among input variables. 
Exposure models that estimate dose by accounting for 
bioavailability need to be developed in concert with PBPK 
models (see Section 4.3.2.1) so that the continuum from 
exposure through disease can be assessed. 

Feasibility. ORD has expertise and a program in 
exposure modeling that is turning its efforts toward children’s 
issues. There are opportunities to combine resources from the 
Children’s Health program with ongoing activities. Exposure 
modeling is also appropriate for the STAR program. An 
intramural effort is required to ensure that ORD addresses the 
specific issues of concern to EPA and to maintain the expertise 
to perform exposure modeling. 

Development and testing of multipathway, 
multichemical models require large amounts of data. Accuracy 
depends heavily on the quality and representativeness of the 
data used to evaluate the input variables. This research area 


is dependent to a large extent on the current field studies being 
completed and the data made available to modelers and 
assessors in a timely fashion. Model development using 
literature and other existing data is feasible now. 

Priority and Rationale. High. EPA is moving toward 
assessment of total exposure for pesticides and other toxic 
chemicals that are found in many environmental media - food, 
drinking water, breast milk, ambient air, indoor air, soil, and 
house dust, for example. The use of a multimedia exposure 
assessment process will improve the quality of children’s 
assessments by reducing the uncertainty of the relationships 
among environmental measurements, biomarker 
measurements, human activities, and toxicological parameters. 
Distribution of exposures in populations is also of increasing 
concern to risk assessors and managers. Computer modeling 
approaches and consideration of multiple pathways is thus of 
high priority for children’s research because these approaches 
are required to identify and quantify risks to children. 

Long-Term Outcomes. A broadly applicable 
probabilistic, total exposure model, capable of linking to a 
PBPK model, will be available to estimate children’s exposure 
to pesticides, producing more accurate assessments of 
children’s exposure and reducing use of default values and 
safety factors in the assessment when sufficient input data are 
available. 

Short-Term Outputs. By 2005, ORD will 

■ Assess children’s total pesticide exposure and refine 
existing exposure models using data from NHEXAS, 
NHANES, and the STAR program. 

■ Analyze models in OPP Standard Operating 
Procedures (Versar 1997) for estimating exposure of 
children to pesticides, identify important pathways of 
exposure, and provide assessment support. 

4.3.3. Methods for Studying Effects and 
Exposure in Humans and Animal 
Models 

This section includes research to develop in vivo and 
in vitro methods of hazard identification for children and 
methods for measuring effects and exposure in children. 

4.3.3.1 In Vivo/In Vitro Methods for Hazard Identification 

Description. Research is needed on the 
development and validation of more sensitive and predictive 
test methods for identifying perturbation of normal development 
by environmental toxicants. The fields of developmental 
biology and toxicology are rapidly progressing to a more 
sophisticated understanding of the basic mechanisms of 
normal development and the way in which these can be 


23 




altered. EPA is focusing more on the use of mode-of-action 
considerations in risk assessment and has included the 
harmonization of cancer and noncancer approaches in its 
research strategies. Most recently, the National Research 
Council released a report entitled Scientific Frontiers in 
Developmental Toxicology and Risk Assessment (NRC 2000), 
which points up the importance of developing and incorporating 
methods that can help in defining and modeling mechanisms 
of developmental toxicity. These methods will not only reveal 
important information on the underlying mechanisms of toxicity, 
but will also provide a more complete analysis of the 
quantitative dose-response relationship of the exposure and 
effect. 

This section should be viewed together with Sections 
4.3.1.1, Biology of Toxicant-Induced Tissue and Organ 
Damage in the Developing Organism, and 4.3.2.1, Methods 
and Models for Using Biological Data in Risk Assessment. 
There will be overlap among these three areas in developing 
future risk assessment methodology. In addition, there should 
be careful coordination between these three areas and the 
research developed under Section 4.3.1.2, Relationship 
Between Exposure to Environmental Agents and Adverse 
Health Effects in Human Populations, to ensure that the 
emerging technology provides the most benefit to the human 
population and that human studies are developing databases 
compatible with laboratory databases. 

Feasibility. This research is very feasible. ORD's 
intramural program has the expertise, and has been involved 
over the years, in the development and validation of sensitive 
and predictive test methods for agent-induced organ/system 
alterations. The STAR program also has supported this effort. 

Priority and Rationale. High. Methods development 
has been and is an important part of EPA's overall research 
program. As noted above, viewed together with Sections 
4.3.1.1,4.3.1.2, and 4.3.2.1, this research will be important for 
EPA to continue its leadership in risk assessment and to 
maintain a current understanding of the databases that will be 
created with the emerging technology. 

Long-Term Outcomes. Mechanism-of-action 
experimentation facilitates the extrapolation of animal and 
experimental model data to humans, enhancing ability to 
predict and study adverse effects in humans. Mode of action 
becomes an integral component of risk assessment. Advances 
in genomics/proteomics are incorporated into EPA’s risk 
assessment methodologies. 

Short-Term Output. By 2005, ORD will 

■ Validate and apply currently available test methods 
and emerging methods in genomics/proteomics and 
molecular biological approaches, useful for 
understanding and elucidating mode of action, in 
developmental toxicity testing. 


4.3.3.2. Methods for Measuring Exposures and Effects in 

Infants and Children and to Aid in Extrapolations 

Between Animals and Humans 

Description. This research will provide measurement 
methods suitable for application in very young children to 
predict health effects currently not detected until later in 
development (i.e., school age). Earlier detection, when 
combined with exposure data, will facilitate the establishment 
of cause-and-effect relationships and provide information 
needed to develop intervention strategies. Development of 
supplemental work in laboratory animals for purposes of 
extrapolation and elucidation of underlying modes of action is 
also included. The research includes tests where the subject 
actively participates and tests where samples, x-rays, or other 
measurements are taken. 

In some cases, such as evaluation of cognitive 
effects, methods currently available for application in school- 
age children will be adapted for use in younger subjects. In 
other cases, such as measures of sensory function (e.g., vision 
and hearing), available methods require further validation prior 
to use in risk assessment. Other research will involve the 
application of available techniques, such as eye-blink response 
and visual contrast, to compare responses of human infants 
and neonatal laboratory animals. Establishment of strong 
predictive relationships between animal tests and outcomes in 
humans may lead to the incorporation of additional evaluative 
endpoints in the standard test batteries used to evaluate 
pesticides and other chemicals under the Federal Insecticide, 
Fungicide, and Rodenticide Act (FIFRA) and TSCA. 

There is a need to develop biomarkers of effects that 
occur either only in young individuals (i.e., developmental^ 
mediated) or with the first exposure (e.g., vaccination 
response). This research will focus on the development of 
biomarker assays for effects expected only in children and 
adaptation of general biomarker assays for use in young 
subjects. Laboratory animals will be used for the development 
of the assays. Validation will require samples from both animal 
and human subjects. Evaluation of biomarkers allows rapid 
and relatively inexpensive determination of potential effects 
following known exposure as well as general screening of 
selected populations for exposure and effect. For example, 
biomarkers of immune system development and competency 
may be useful in the prediction of increased susceptibility to 
asthma or allergy in very young children. 

There is also a need to revise currently available 
biomarker assays for use in epidemiology studies focused on 
young children. In many assays, the medium (e.g., serum or 
urine) or needed quantity of the sample (e.g., 100 mL) makes 
a standard biomarker assay unsuitable for use in infants and 
young children. Methods adapted to provide data with minimal 
intrusiveness and discomfort are needed for young children, 
such as breath measurements and analytical methods for small 


24 




quantities of blood obtainable from a finger prick. 

In addition, new methods are required for a range of 
exposure-related research issues. Because of the high cost of 
field studies, it is important to develop the most accurate and 
cost-effective methods of sampling and chemical analysis and 
of conducting questionnaire surveys. Consideration of the 
successes and limitations of past and current field studies and 
questionnaire surveys will lead to better methods. Issues such 
as the ability to detect and quantify substances above levels of 
concern in environmental and biological samples, the ability to 
analyze for speciation and metabolites, and the ability of 
sampling protocols to capture intermittent high exposures, 
longer-term average exposures, and personal total exposures 
need to be addressed. Cost-effective screening methods using 
questionnaires and simple sampling methods are also needed. 
Dermal exposure methods are needed for surface transfer, 
adhesion, adsorption, and ingestion from hand-to-mouth and 
object-to-mouth transfers of contaminants. Methods for 
improving survey response rates and for collection of activity 
data are needed. Development of a cost-effective, feasible 
protocol for biological and residential environmental sampling 
for children is needed. 

Feasibility. Expertise to conduct biomarker research 
is available in the NHEERL Experimental Toxicology, 
Neurotoxicology, Reproductive Toxicology, Environmental 
Carcinogenesis, and Human Studies Divisions. ORD currently 
has a small program investigating the development of immune 
system biomarkers. An effort to develop cholinesterase assays 
requiring smaller quantities of blood, and therefore suitable for 
use in children, is in the pilot phase in NHEERL under the 
Sensitive Subpopulation program. Other agencies, such as 
CDC and NIEHS, have an interest in the application of this 
work but, other than specific cancer biomarker work underway 
at NCI, no focused research program is funded. CDC is 
developing methods to screen for multiple pesticides in smaller 
serum samples suitable for use in children. NERL develops 
methods for survey design and implementation and methods 
to measure contaminant concentrations in environmental 
media. The STAR program solicited proposals for research on 
biomarkers for the assessment of exposure and toxicity of 
children and will award grants in 2000. 

Priority and Rationale. Medium . Better methods of 
sampling, analysis of samples, and test protocols for infants 
and children will support the collection and generation of better 
data for risk assessment. A separate program in methods 
development, although valuable, is somewhat less directly 
related to answering questions about risk than are the studies 
in which the methods will be used. In the Children’s Health 
program, methods development needs to take place within a 
larger study with broader objectives. For example, methods 
development in exposure measurements, recruitment and 
retention of study participants, and assessment of 
neurobehavioral toxicity is being conducted as part of the pilot 
studies for the Longitudinal Cohort Study. 


4.3.4. Risk Management Research and Risk 
Communication 

This section discusses research to reduce 
environmental risks to children through development of control 
and cleanup technologies, prevention of risk, and approaches 
to community education and intervention. 

4.3.4.I. Multimedia Control Technologies That Account 

for the Susceptibilities of Children 

Description. This research area will build upon 
existing methodologies, which range from drinking water 
treatment to air emission controls to bioremediation and 
phytoremediation. The new focus on children's health issues 
highlights the dichotomy that often exists in risk management. 
Frequently, EPA must respond to a crisis caused by an 
environmental agent without having a risk assessment to 
provide the quantitative goals for risk reduction. For example, 
recent outbreaks of cryptosporidiosis, an infection caused by 
exposure to the Cryptosporidium microbe, usually through 
ingestion of contaminated drinking water or food, have required 
immediate efforts to remove the microbe from drinking water. 
Children, the elderly, and those with compromised immune 
systems are particularly susceptible to cryptosporidiosis, even 
to the extent of being at risk of death. Acceptable 
concentrations of Cryptosporidium in drinking water for children 
and other susceptible subpopulations have not yet been 
determined through risk assessment. Until such levels are 
established and the technology is available to achieve them, 
efforts will continue to refine and modify existing methods of 
drinking water treatment so that devastating outbreaks do not 
occur and children are protected. For example, ORD is 
working toward the goal of having water treatment methods 
that will reduce concentrations of protozoan oocysts and 
bacterial spores in raw water by six orders of magnitude. 

Children are hypothesized to be particularly 
susceptible to pesticides, and nonpoint source runoff 
containing pesticides often contaminates areas attractive to 
children, such as streams and ponds. Research will be 
conducted on utilization of microorganisms and plants to treat 
nonpoint source contamination resulting from spray drift of 
pesticides and residual pesticides. Strategic placement of 
selected plants can offer means to interdict water flows 
contaminated with pollutant chemicals occurring as part of 
runoff or contaminated subsurface waters. Use of selected 
plants or microorganisms may result in reduction of chemical 
pollutants and provide active land restoration options. 

In addition to these treatment technologies, particular 
attention will be directed to air treatment methods including 
treatments for the indoor environments in which children's 
inhalation exposure may be different from that of adults. 

Feasibility. ORD has expertise in the development 
of engineering solutions to respond to children’s health 


25 




problems. Research in control technology for water, air, and 
hazardous waste is conducted at the NRMRL. 

Priority and Rationale. Low for the Children’s Health 
program. Although it will contribute to reducing risks to 
children, research in control technology is not a specific 
children’s issue and is more appropriately conducted under the 
ORD research programs for Air, Water, Hazardous Waste, and 
Pesticides and Toxics. 

4.3.4.2. Methods for Reducing Exposure Buildup of 

Contaminants in Indoor Environments 

Description. Children spend most of their time in 
indoor environments. Contaminants in air and on surfaces are 
expected to result in significant childhood exposures. 
Consumer products that are used indoors, such as pesticides, 
cleaning products, building materials, and floor coverings, may 
release toxic agents into a child’s environment, causing 
exposure. This exposure can be reduced by cleaning up the 
contaminants after they have been released. It may also be 
reduced by designing consumer products that use or release 
smaller amounts of toxic materials. 

Recent occurrences of household applications of 
methyl parathion, in which residents, particularly children, were 
placed at risk, serve as useful examples of the need for 
development of methods and processes to remove pesticides 
and other toxic compounds from structures. Children, 
especially infants and toddlers, may be highly exposed to 
chemicals that accumulate in carpets and construction joints 
and cracks near the floor. Accumulations of methyl parathion 
resulted in the demolition and disposal of many structures, 
including homes and day care centers, because no methods 
exist for the removal of chemicals from structures. High 
exposures can also be discovered during epidemiology and 
exposure studies, and ORD must be able to provide individuals 
and public health departments with assistance in reducing 
exposures where possible. This research area will focus on 
methods to reduce exposure to indoor contaminants through 
cleaning, encapsulation, chemical deactivation, and other 
approaches that will be more cost effective than demolition and 
disposal. 

Feasibility. It is feasible to conduct this research in 
the ORD intramural program. Although no work is currently 
being done in this area, research in the areas of reactive gates 
and iron-sediment washing may be directly applicable. 

Priority and Rationale. High, The impact of 
developing and applying specific procedures for dealing with 
accidental methyl parathion applications within homes will be 
highly significant. Recent episodes involving children have 
occurred in urban settings, primarily as the result of illegal 
application in homes by unlicensed pesticide applicators. In 
this specialized setting, the only appropriate solution was to 
evacuate the homes and destroy them. In a large-scale 


outdoor setting, chemical oxidation and neutralization 
methodologies have been successfully applied at the Gila River 
site in Arizona for treatment of methyl parathion, and it is 
feasible that these methodologies could be modified for use in 
a domestic setting. 

In addition to these specific child-related problems 
with methyl parathion, recent studies in agricultural States have 
indicated that farm children are exposed within their homes to 
levels of pesticides that are seven to ten times higher than 
outdoors, specifically chlorpyrifos and endosulfan. Even 
though the most pressing need is for specialized techniques for 
treating methyl parathion in the confined setting of homes, it is 
quite plausible that these technologies could be further 
modified for use with other pesticides. 

Development of cost-effective methods for reducing 
exposure and risk occurring via child-specific pathways such as 
dermal and hand-to-mouth contact has several advantages that 
make it a high priority for ORD. It will help the EPA Regions to 
provide solutions to the public for known and possible health 
risks to children in indoor environments. On a chemical- 
specific basis where risk reduction methods can remove 
exposure, such research may even avoid the need for further 
risk assessment research. In addition, ORD needs to be able 
to advise and assist individual study subjects in EPA- 
sponsored epidemiology and exposure studies who are found 
to be highly exposed within their residences, day care centers, 
and schools. 

Long-Term Outcome. Broadly applicable methods 
for removing chemicals from residential environments and for 
preventing exposure in the residential environment (e.g., 
through encapsulation) are used by the Superfund program, 
EPA Regional Offices, State and local public health and 
environmental agencies, and others to achieve cost-effective 
cleanup to safe levels for children. 

Short-Term Output. By 2005, ORD will 

■ Develop a method to remove pesticides and other 

chemicals from building structures and carpets or to 
prevent exposure (e.g., through encapsulation), 
using methyl parathion as a prototype. 

4.3.4.3. Communication of Risks and Development of 
Risk Reduction Techniques Through Community 
Participation 

Description. ORD will support research on methods 
of education and intervention that encourage and offer 
assistance to members of communities working together to 
reduce risks to their children. Examples include projects where 
researchers work with the community to reduce children’s 
exposure to pesticides at home and at school, intervention 
programs to help parents reduce the likelihood of asthma 
attacks in their children, community-based studies to determine 


26 





which types of intervention are most successful, dissemination 
of information to medical personnel, and studies of how to 
communicate risks and risk reduction methods most effectively 
to diverse groups of people. For example, dialogue could be 
initiated between scientists and the community regarding 
infectious disease threats to children such as E. coli strain 
0157. 

An effective exposure or epidemiology study will 
involve the community being studied. Through civic and 
religious groups, teachers and day care workers, primary care 
physicians, and other community members, researchers can 
enlist the community in study design and'implementation, 
advertise the study and recruit participants, and communicate 
results. It is important for researchers to understand and to be 
sensitive to cultural practices, to address anxiety related to the 
study or to real or perceived environmental hazards, and to 
assist local public health departments in dealing with problems 
that are found, such as the need for alternate food or water 
sources or for remediation and treatment interventions. 

Feasibility. The eight Centers for Children’s 
Environmental Health and Disease Prevention have projects in 
risk communication, intervention, and reduction. There is little, 
if any, expertise in this area within the ORD intramural 
program, except to the extent that individual scientists have 
dealt with some of these issues in epidemiology and exposure 
studies. In any future studies of children, ORD will provide for 
community involvement, communication of study results to the 
respondents, advice about lowering exposures, and 
cooperation with local public health departments to reduce 
risks where necessary. 

Priority and Rationale. High. Developing cost- 
effective methods for reducing children’s exposures and risks 
through education and community involvement has several 
advantages that make it a high priority for ORD. It will help 
EPA Regions to provide solutions to the public for both known 
and possible health risks to children. This research will also 
improve ORD’s ability to advise and assist individual study 
subjects who are found to be highly exposed in EPA-sponsored 
epidemiology and exposure studies. It is recommended that 
research in this area continue to be conducted underthe STAR 
program. Any intramural efforts should be planned as part of 
an exposure or epidemiology study, rather than a separate 
research program. 

Long-Term Outcome. Through implementation of 
better methods of communicating scientific information about 
risk and working with communities to reduce risk, EPA 
strengthens its community-based risk assessment and risk 
management programs. 

Short-Term Outputs. By 2005, ORD will 

■ Implement risk intervention programs in several 

communities and publish journal articles on 


effectiveness of risk intervention approaches (output 
of STAR program Centers for Children’s 
Environmental Health and Disease Prevention). 

■ Compare methods for communicating risks of 

pesticides on foods (output of current STAR program 
grant). 

4.3.5. Cross-Cutting Issues 

4.3.5.1. Variation in Susceptibility and Exposure in 
Children 

Description. Variation in susceptibility and exposure 
within an age group may be as important as variation between 
groups. Factors such as genetic traits, pre-existing disease, 
nutrition, behavioral traits, medications, coexisting exposures, 
sex, and ethnicity may result in great variation in risk within an 
age group. Epidemiological and clinical studies, animal 
toxicology studies, and in vitro assays are important methods 
to identify and assess factors that may contribute to observed 
variability in susceptibility. Exposure studies that first identify 
scenarios and pathways of greatest concern and then perform 
the research to fill the data gaps will also be useful. 

This research area is closely related to the laboratory 
and field studies described in Section 4.3.1. Two exposed age 
groups might exhibit the same means, but their statistical 
variation may be different. Researchers need to look at the 
individuals in the high ends of distributions within age groups 
for clues to toxic mechanisms, adverse health effects, and high 
exposures. 

This research area covers issues related to variation 
in susceptibility and exposure that are unlikely to be 
systematically examined underthe research areas in Section 

4.3.1, although they may be part of a study of a particular 
environmental agent or endpoint. 

Feasibility. Variation in susceptibility and exposure 
to environmental agents is a major focus of ORD’s Human 
Health Risk Assessment program. Many of the issues that 
might be addressed here are also being addressed in other 
research areas. Current and planned ORD exposure and 
epidemiology studies, for example, address exposure and 
sometimes effects in groups of children hypothesized to be 
highly exposed, including children living in agricultural areas 
and inner cities. Research into modes of action will of 
necessity examine why some individuals respond to exposure 
while other individuals exposed at the same level do not. For 
example, a compromised immune system in the form of 
allergies to environmental pollutants is being studied as a 
potential major cause of asthma. Interactions between 
environmental agents and genes will be important in studying 
modes of action and in using such data to assess risk. 

Priority and Rationale. Medium. Given the limited 


27 





knowledge about which are the vulnerable ages and how and 
why individuals in these age ranges tend to be vulnerable, and 
the fact that many issues related to variability will be addressed 
in other research areas, the science team concluded that this 
area was not of as high a priority as other areas in its potential 
contribution to reducing uncertainty in risk assessment. Some 
of the research described in this area, such as variation related 
to genetic traits and high exposures, will be carried out under 
other research areas. As more becomes known about how 
children’s vulnerabilities and exposures differ from those of 
adults, the priority of issues such as the impact of nutrition, 
behavior, and co-existing disease on susceptibility will 
increase. 

4.3.5.2. Cumulative Risks to Children 

Description. Children are exposed to many 
environmental compounds simultaneously. Mixtures of 
chemicals indoors, in the air, and on surfaces come from a 
variety of sources, including outdoor air and outdoor dust, 
indoor heating sources, building materials, and consumer 
products. Volatile organic air pollutants occur in mixtures with 
ozone. Mixtures of heavy metals and organic pollutants at 
waste sites can contaminate ground water, surface water, 
drinking water, and residential areas both indoors and out. 

Historically, toxicity testing, mechanistic research, 
human studies, risk assessments, and many of EPA’s 
regulations have been directed at single chemicals. There is 
little information on the effects on children of simultaneous 
exposure to many environmental agents, let alone any 
information on the toxicokinetics and toxicodynamics of 
chemical interactions in this population group. As a first step, 
research is needed to compare the individual toxicokinetics and 
toxicodynamics of known developmental toxicants to those of 
simple mixtures of two or three of the same chemicals in 
animal models. The selection of chemicals should be made on 
the basis of the availability of similar information on mature 
animals. 


Methods of estimating both aggregate exposure to 
mixtures and dose-response relationships are not generally 
available and need to be developed. 

Feasibility. EPA is starting to address the issue of 
cumulative risk, but methods are not well developed. EPA's 
Risk Assessment Forum is developing guidelines for 
cumulative risk assessment. ORD has sponsored studies of 
exposure to multiple chemicals and chemical classes under 
NHEXAS. Research on the effects of exposure to mixtures 
and how such data can be used in risk assessment will be a 
major focus of ORD’s Human Health Risk Assessment 
program. The STAR program and NIEHS are co-sponsoring 
a research program on chemical mixtures in environmental 
health. OPP is developing a risk assessment of 
organophosphate pesticides with like modes of action. These 
efforts are not focused on children’s issues, but rather on 
learning as much as possible about health effects of mixtures. 
Methods for cumulative risk assessment are not well 
developed. 

Priority and Rationale. Medium. Given the current 
lack of knowledge about which are the vulnerable ages and 
how and why individuals in these age ranges tend to be 
vulnerable, as well as the general lack of knowledge about the 
biological effects of exposure to mixtures, this area is a lower 
priority for the Children’s Health Program.. 

4.4. Linking and Summary of 
Research Areas 

The preceding sections have focused on each 
separate research area. Table 2 is an overview of Section 4.3 
containing a short description of each research area, the 
contribution of the research to EPA’s risk assessments and risk 
management decisions, and its relation to other research 
areas. 


28 





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33 












5. GUIDANCE FOR IMPLEMENTATION 


The strategy will be implemented by ORD’s three 
national laboratories and two national centers. Approximately 
75% of the extramural resources of the Children’s Health 
program are expected to be dedicated to investigator-initiated 
grants under the STAR program. The intramural program will 
be conducted by ORD scientists supported by the remaining 
25% of the extramural funding. Research on children’s issues 
performed to address specific concerns of EPA Program 
Offices, such as epidemiology studies conducted for the air 
program and exposure studies conducted for the pesticides 
program, will continue. 

Criteria for selection of research projects and topics 
for extramural RFAs have been adapted from criteria proposed 
in the ORD Ecological Research Strategy (EPA, 1998h). ORD 
will undertake projects that meet the following criteria: 

■ The project is directly related to assessing or reducing 
risks to children. 

■ Intramural projects address research areas identified 
as of high priority in this strategy. 

■ Extramural STAR projects address research areas 
identified as of high or medium priority in this strategy. 

■ The project is consistent with a short- or long-term 
need of an EPA program. Long-term needs include 
the development of data, models, and methods for 
using biological information in risk assessment. 

a The project allows ORD to establish or maintain a 

core competency and ability to meet future needs. 

The expertise needed for this research program is 
distributed throughout ORD. Interdisciplinary research across 
a diverse and geographically dispersed organization such as 
ORD is a challenge. Collaborations across ORD laboratories 
and centers are essential to successful implementation. Figure 
2 shows an example of the type of collaborations that the 
strategy encourages--a combined exposure and epidemiology 
study of children in a population along the U.S.-Mexico border 
conducted by NERL and NHEERL. 

ORD scientists are also encouraged to become 
familiar with relevant research in the STAR program. There 
are opportunities for ORD scientists to participate in developing 
RFAs for extramural grants, reviewing proposals that are highly 
rated in external peer review, attending meetings of 
investigators, and even collaborating with investigators in 
appropriate situations. Figure 3 shows an example of a 
collaboration between ORD, the Minnesota Department of 
Public Health, a nonprofit consortium operating under 
NHEXAS, and a grantee under the STAR program. 


Figure 2. Pesticides in Young Children along the 
U.S.-Mexico Border: A NERL/NHEERL 
Collaboration 

This project assesses the relationship between 
health outcomes in young children along the U.S.-Mexico 
border and repeated pesticide exposures via multiple 
sources and pathways. NERL and NHEERL formed a 
partnership with a co-chair from each laboratory and joint 
planning, implementation, participation of staff, and peer 
review and publication. 

Preliminary studies included review of existing 
data, development of geographic information system 
maps of the area, and a workshop to identify relevant 
health endpoints and appropriate epidemiology studies. 
Methods of screening of infants and children are now 
being identified and implemented. More extensive 
exposure screening will then take place, and if warranted 
by the results, an epidemiology study will be conducted to 
assess the relationship between exposures and specific 
health endpoints. 


Coordination and collaboration with other Federal 
agencies are keys to successful implementation. One 
mechanism for collaborating with other Federal agencies is 
EPA’s continued leadership of and participation in the U.S. 


Figure 3: Pesticides and Children in Minnesota: 
A NHEXAS Study and a STAR Grant 

Underthe NHEXAS Program, ORD sponsored a 
study under cooperative agreement with Research 
Triangle Institute and the Environmental and Occupational 
Health Sciences Institute in which environmental, 
personal, and biological samples were collected and 
analyzed for pesticides and a questionnaire was 
administered for a sample of children in Minneapolis-St. 
Paul. The State of Minnesota also participated. An 
investigator at the University of Minnesota proposed a 
study under the STAR program for a population of the 
same age in rural Minnesota. At the grantee's instigation, 
the two studies used similar protocols so that the results 
can be compared. 


Task Force on Children’s Environmental Health Risks and 
Safety Risks. The Task Force, chaired by the EPA 
Administrator and the Secretary of Health and Human 
Services, was established by Executive Order in 1997 (U.S. 
Executive Order No. 13045 1997). The members of the Task 


34 






Force are Federal agencies with programs that address 
children’s environmental health and safety, including EPA; ten 
Institutes of NIH; CDC; ATSDR; FDA; the Departments of 
Education, Labor, Justice, Energy, Housing and Urban 
Development, Agriculture, and Transportation; the Consumer 
Product Safety Commission; and the Office of Science and 
Technology Policy. 

Through the efforts of the Task Force Working Group 
on Developmental Disorders, EPA, NICHD, NIEHS, and the 
National Institute of Dental and Craniofacial Research (NIDCR) 
are sponsoring a joint RFA to study susceptibility and 
mechanisms of human congenital malformations, including 
research on the contribution of genetic and environmental 
factors, identified at the molecular level, to the etiology, 
distribution, and prevention of disease within families and 
across populations. As discussed in Section 4.3.1.2, the 
working group is also actively exploring the feasibility of 
establishing a longitudinal birth cohort, as a joint effort of the 
concerned Federal agencies. Through the Task Force, EPA 
and the Department of Health and Human Services also 
developed a national strategy to address childhood asthma. 

Other examples of EPA’s collaborations include the 
Centers for Children’s Environment Health and Disease 
Prevention cosponsored with NIEHS, sponsorship of special 
exposure studies in CDC’s NHANES on urine levels of 


pesticides in children and adults and levels of persistent 
organic compounds in adolescents, and collaboration with CDC 
and FDA in the NHEXAS study of children in Minneapolis-St. 
Paul. 

Information on Federal research and EPA activities 
can now be found on the Internet. The ORD home page 
provides electronic copies of publications, including research 
strategies. The OPP home page posts issue papers and 
deliberations of the OPP Science Advisory Panel on children’s 
risk issues. Several agencies, including NIEHS, CDC, NCI, 
and the ORD STAR program, publish current budget requests 
and descriptions of their research programs and initiatives and 
provide lists of their intramural and extramural research. 
CHEHSIR, which reports on Federal research on children’s 
environmental health and safety risks at a project level, is 
online (EPA 2000b). ORD managers and scientists are 
encouraged to consult these online sources to learn about 
Federal research and activities on children and to provide 
similar information on their Internet home pages. 

Figure 4 summarizes principles for implementation of 
the strategy. 


— 

Figure 4. Guiding Principles for Implementation 

■ When designing a research study, investigators should consider the impact of the results on EPA risk 
assessments for children. Requests for Applications (RFAs) in ORD intramural and STAR programs should ask 
investigators to specify the potential impact of results on the EPA risk assessment process. 

■ A multidisciplinary research program that is coordinated across the ORD laboratories and centers is encouraged. 
RFAs for cross-laboratory/center intramural projects and fostering of contact between extramural grantees and 
ORD scientists are encouraged. 

■ Outreach, coordination, and partnership with other Federal agencies is essential, particularly in the areas of 
human studies and biological mechanisms of action. 

■ Toxicologists, epidemiologists, clinicians, and exposure scientists are encouraged to work collaboratively during 
all phases of research planning, development, and implementation. 

■ ORD needs to develop and maintain intramural expertise to be able to incorporate new data and methods into 
EPA risk assessments. Use of biological data in risk assessment is a high priority. A stable intramural research 
program with adequate support is essential to achieving this capability. 

■ Research across more than one endpoint point is encouraged where possible, such as research on mechanisms 
that can lead to multiple endpoints and endpoints affecting the same target organ. 

■ Risk reduction research and risk management goals should be considered throughout the course of this program. 


35 




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NCI. (National Cancer Institute). 2000. Home page. 
www.cancer.gov/. 

NHLBI. (National Heart, Lung, and Blood Institute). 2000. 
Framingham Heart Study home page. 
http://www.nhlbi.nih.gov/about/framingham/index.html. 
NICHD. (National Institute of Child Health and Human 
Development). 2000. Home page: www.nih.gov/nichd/. 
NIEHS. 2000a. (National Institute of Environmental Health 
Sciences). National Toxicology Program home page. 
http://ntp-server.niehs.nih.gov/ 

NIEHS. 2000b. Environmental Genome Project home page. 

(EGP). http://www.niehs.nih.gov/envgenom/. 

NIEHS. 2000c. Research initiatives: children’s health - cleft 
palate birth defects, www.niehs.nih.gov/external/resinit/ri- 
27.htm 

NIEHS. 2000d. First national survey shows Americans’ 
bedding can make them sick: allergens the culprit. Press 
release, May 9, 2000. 

NIEHS. 2000e. Asthma and allergy prevention: risk 
assessment: The National Allergen Survey. 
http://www.niehs.nih.gov/airborne/research/risk.html. 
NRC. (National Research Council). 2000. Scientific Frontiers 
in Developmental Toxicology and Risk Assessment. 
Washington, DC: National Academy Press. 

NRC. 1994. Science and Judgement in Risk Assessment. 

Washington, DC: National Academy Press. 

NRC. 1993. Pesticides in the Diets of Infants and Children. 

Washington, DC: National Academy Press. 

NRC. 1983. Risk Assessment in the Federal Government: 
Managing the Process. Washington, DC: National 
Academy Press. 

NRDC. 1997. Our Children at Risk: The 5 worst 
environmental threats to their health. San Francisco, CA: 
Natural Resources Defense Council. 

Rodier, P.M. 1980. Chronology of neuron development: 
animal studies and their clinical implications. Dev. Med. 
Child Neurol. 22:525-545. 

US Executive Order No. 13045. 1997. On protection of 

children from environmental health risks and safety risks. 
The White House, April 21, 1997. EPA.600-R-97-915. 
Versar, Inc. 1997. Standard operating procedures (SOPs) for 
residential exposure assessments. Draft report. 
Washington, DC: U.S. Environmental Protection Agency, 
Office of Pesticide Programs. 

WHO. (World Health Organization). 1986. Phnciplesfor 


37 



Evaluating Health Risks from Chemicals During Infancy and 
Early Childhood: the Need for a Special Approach. 
Environmental Health Criteria 59. Geneva, Switzerland: World 
Health Organization. 


38 




APPENDIX A. GROWTH AND DEVELOPMENT FROM BIRTH 

THROUGH ADOLESCENCE 


At birth, most organs and systems of the body have 
not achieved structural or functional maturity. Physical growth 
and functional maturation continue through adolescence, with 
the rates of growth and functional maturation varying among 
the different tissues, organs, and systems of the body. There 
are specific periods or windows of vulnerability during 
development when toxicants can permanently alter the function 
of a system (Bellinger et al. 1987, Roder 1995). Although 
these critical periods often occur during gestation, some 
systems that continue to mature postnatally may be adversely 
affected by exposure to toxicants after birth. Organs and 
systems that continue to undergo maturation during infancy 
and childhood include the lungs, kidneys, and liver, and the 
immune, nervous, endocrine, reproductive, and gastrointestinal 
systems (Dobbing and Sands 1973, Hoar and Monie 1981, 
Andersson et al. 1981, Langston 1983). It is important to 
emphasize that a physiological or functional perturbation during 
a critical period of development increases the overall risk 
associated with childhood environmental exposure. For 
example, exposure to a neurotoxicant that adversely impacts 
cognitive function is integrated over a lifetime when applied to 
a child (Gilbert and Grant-Webster 1995). 

Differences in susceptibility between children and 
adults may be due to either qualitative or quantitative 
differences in the toxicity of an environmental agent. 
Qualitative differences in toxicity between children and adults 
are a result of structural or functional alterations that occur as 
a consequence of exposure during a particularly vulnerable 
period of organ or system development. On the other hand, 
quantitative differences are due in part to age-related 
differences in pharmacokinetic and pharmacodynamic 
processes. The alterations induced may be immediately 
apparent or may manifest as delayed toxicity later in life as a 
result of short-term or low-level exposure during development. 
An example of delayed toxicity, due to enhanced susceptibility 
during development, is the increased incidence of vaginal and 
cervical cancers in the daughters of mothers who took 
diethylstilbestrol (DES) to prevent miscarriage during 
pregnancy (Herbst et al. 1972). Another example is the 
exposure of newborns to chloramphenicol which resulted in 
cyanosis, progressive circulatory collapse, and ultimately 
death, and which was attributed to decreased clearance of this 
chemical (Weiss et al. 1960). Decreased metabolic and 
excretory capacity of newborns has also been associated with 
the increased toxicity of other chemicals during the postnatal 
period. These include the "gasping syndrome" associated with 
benzol alcohol-preserved drugs (Gershanik et al. 1982) and 
neurological damage and death as a result of dermal 
application of hexachlorophene-contaminated talcum powder 
(Hay 1982). Cases of infant poisoning and death by 
hexachlorobenzene have also been reported following 


ingestion of highly contaminated human milk (Peters 1976). 
The consumption of mercury-contaminated fish by nursing 
mothers resulted in severe neurological disorders in their 
breast-fed infants (Amin-Zaki et al. 1980). The antibiotic 
tetracycline produces tooth discoloration and enamel 
hypoplasia as well as interfering with bone growth in infants 
prior to first dentition and in children prior to permanent 
dentition (Kacew 1992). 

The lungs are the major portal of entry of volatile and 
airborne chemicals. The lungs are structurally immature in 
neonates and continue to mature during early childhood. Not 
until several years after birth is the full complement of mature 
cells in the lungs achieved (Langston 1983). There is little 
information available on the pulmonary absorption and 
bioavailability of inhaled chemicals in infants and children. 

Ingestion is a major route by which infants and 
children are exposed to environmental chemicals. Absorption 
of chemicals from the gastrointestinal tract is influenced by 
factors such as the total mucosal surface area, pH, perfusion 
rate, blood supply, and the gastric emptying and intestinal 
transit time. All of these factors change during postnatal 
development (WHO 1986). Consequently, the absorption of 
some chemicals is greater in infants than in adults. For 
example, lead is absorbed better by infants than by adults 
(Ziegler et al. 1978). The rates of activation and deactivation 
of chemicals are also related to the stages of maturation and 
development of enzyme activity (Besunder et al. 1988). 

Chemicals also enter the body via absorption through 
the skin. The surface area to body weight ratio of children is 
much greater than that of adults. As such, the total body 
dermal dose to a chemical for a young child can be as much as 
two to three times greater, on a per-unit body-weight basis, 
than for an adult (Wester and Maibach 1982). The EPA interim 
report on dermal exposure assessment (EPA 1992) indicates 
that this may be the primary difference between adults and 
children with respect to dermal absorption. The data available 
on childhood or comparable laboratory animal exposures via 
the dermal route are limited (NRC 1993). 

The structure and function of the kidneys are 
immature at birth (Dean and McCance 1947). This is an 
important consideration, given that the elimination of most 
chemicals from the body occurs primarily via renal excretion. 
Both glomerular and tubular function increase with age in the 
infant, with glomerularfunction somewhat more advanced than 
renal tubular function in the neonate (NRC 1993). 
Reabsorption of chemicals from the tubular lumen into tubular 
cells also varies with age. Weak organic acids are more 
readily reabsorbed by the infant than the adult. Some metals 


A-1 



(i.e., cadmium, mercury, and manganese) depend on the 
kidneys for their elimination. The elimination of these metals 
by neonatal rats is less than that in adults (Kostial et al. 1978). 
Smaller proportions of absorbed lead are also excreted via the 
renal route in infants compared to adults (WHO 1986). 
Because chemical excretion by the kidneys is dependent 
primarily on glomerular filtration, tubular secretion, and 
reabsorption, a decrement due to the immaturity of any of 
these functions in the infant may result in delayed clearance of 
a chemical from the body. Consequently, an increased risk of 
toxicity may ensue from the prolonged presence in the body of 
a chemical or its active metabolite(s) (Braunlich 1981). 
Unfortunately, there is only limited information about age- 
related differences in elimination of environmental chemicals in 
experimental animals, let alone in humans (NRC 1993). 

As with other organs, development of the liver 
involves a series of integrated structural and functional 
changes that continue postnatally. This includes tissue cell 
composition, hepatocyte differentiation, and the appearance of 
hepatic enzyme activity. After birth the parenchymatous cells 
outnumber all other types of cells in the liver (WHO 1986). 
Another important cell type in the neonatal liver is the 
hemopoietic cell, as the liver is the site of hematopoiesis prior 
to birth (Owen 1972). Biotransformation of organic chemicals 
via phase I and phase 11 metabolic reactions is generally slower 
in the neonate than in the adult. Consequently, degradation 
and elimination of chemicals that are dependent on these 
biotransformation reactions are generally reduced in infants 
compared with adults. Different isoenzymes and enzymes also 
mature at different ages. Maturation of mechanisms 
responsible for the biotransformation of organic chemicals 
varies for each reaction and chemical (Klinger 1982). 
Examples of toxicities associated with the newborn's 
decreased ability to conjugate and eliminate chemicals include 
chloramphenicol (Sutherland 1959), diazepam (Nau et al. 
1984), and hexachlorophene (Tyrala et al. 1977). 

Children are more vulnerable because they have less 
ability to metabolize and excrete some environmental 
pollutants. Young children have higher resting metabolic and 
oxygen consumption rates than do adults, which are related to 
a child's rapid growth and larger cooling surface area per unit 
weight (Hill 1964). During the first 4 to 6 months of age an 
infant gains weight more rapidly than during the rest of its life 
(Tanner et al. 1966). Adolescent children are also growing and 
adding new tissue at a more rapid rate than are adults. 
Because of rapid growth during infancy and puberty, 
accumulation of chemicals in the body may be greater than 
during adulthood, when growth is less rapid. Respiratory and 
circulatory flow rates as well as energy and fluid requirements 
are greater in infants and young children than in adults, giving 
rise to a greater potential for respiratory and intestinal exposure 
to chemicals per unit body weight (WHO 1986). 

The nervous system is not fully developed at birth and 
continues to mature postnatally. During the first years of life, 
rapid brain growth occurs, with approximately 75% of the full 
complement of brain cells of all types present by approximately 
2 years. The adult equivalent number of neurons is achieved 


by 2 years; however, complete myelination does not occur until 
adolescence. The brain weight of a 6-month-old infant is 
approximately 50% that of an adult's and approaches adult size 
by early childhood. In contrast, behavioral and physiological 
development of the brain continues into later childhood (Roder 
1980, 1995; NRC 1993). 

Because behavioral development is dependent on 
physical and functional maturation of the nervous system, 
chemical-induced toxic effects, which occur during critical 
periods of maturation, may permanently alter behavioral 
development. The various stages of nervous system 
development, which include differentiation, proliferation, 
migration, synaptogenesis and axonal growth, and myelination, 
all represent potential targets for chemical-induced 
neurotoxicity (Roder 1995). For example, myelination of nerve 
tracts in the spinal cord and peripheral nerves, which is a 
process that is not complete until puberty, may be affected by 
certain chemicals. Examples of the vulnerability of the 
developing nervous system include prenatal and early 
childhood exposure to lead, radiation therapy in children under 
4 years old, and elevated serum bilirubin levels in neonates. 
Certain chemical toxicants that also have been implicated in 
causing effects on the developing nervous system include 
ethanol, mercury, polychlorinated biphenyls, and certain 
organophosphates (Schull et al. 1990, Chakraborti et al. 1993, 
Igata 1993, Needleman 1995, Jacobson and Jacobson 1996). 

The developing endocrine system may be directly 
affected by chemicals or indirectly affected by chemical 
interactions, with some step of the regulating axis controlled by 
the hypothalamus, pituitary, or other part of the brain 
(McLachlan et al. 1981). The reproductive system, as well as 
other systems, can also be affected by chemical interactions 
with the neuroendocrine organs. For example, exposure of 
experimental animals to chemicals with estrogenic or 
androgenic activity during the early postnatal period can alter 
the sexual dimorphic pattern (Barraclough 1966). Exposure to 
chemicals with androgenic or estrogenic activity may also alter 
growth and time to onset of puberty (Saenz de Rodriguez and 
Toro-Sola 1982). Altered neuroendocrine function may also 
affect adrenal corticosterone release (Libertun and Lau 1972). 

The immune system is not fully developed at birth. 
Consequently, full-term infants are immune deficient as 
compared with older children and adults in essentially all 
measurable immune parameters, resulting in their increased 
susceptibility to infections (Andersson etal. 1981). Both innate 
and specific immune responses of infants and children are 
suboptimal compared to those of adults. For example, natural 
killer cell activity is at about 60% of adult levels in newborns 
(Toivanen et al. 1981) and complement activity does not reach 
adult levels until about 6 months of age (Colten 1977). As for 
specific immune responses, certain T helper cell functions only 
reach adult levels by 6 months of age (Miyawaki et al. 1981). 
Whereas the ability of B cells to produce antibodies of the IgG 
and IgA classes increases with age, adult levels are reached 
only by 5 and 12 years of age, respectively (de Mauralt 1978). 
In addition, external factors play a role in the maturation of the 
immune system. For example, immune responsiveness and 


A-2 



maturation of newborns is influenced by active (i.e., 
vaccination) and passive (i.e., food, environment) exposure to 
antigens during perinatal development. Defects in the 
development of the immune system due to heritable alterations 
in lymphoid elements have provided clinical and experimental 
examples of the consequences of impaired immune 
development (Heise 1982). 

While information on developmental toxicity following 
in utero exposure far exceeds that of developmental toxicity 
following exposure of the newborn and young animal, there are 
data that indicate the vulnerability of the developing animal to 
toxic-induced perturbations. It was recently recommended that 
testing be performed in appropriate animal models during the 
postnatal developmental period and that adverse effects that 
might become evident be monitored over a lifetime. It was also 
indicated that the nervous, immune, and reproductive systems 
were of particular importance for testing given the existing 
database (NRC 1993). For example, certain organophosphate 
and carbamate cholinesterase-inhibiting pesticides affect 
learning and behavioral development as well as development 
of the visual system. Other chemicals that affect the 
developing nervous system include methyl mercury, ethanol, 
methylazoxymethanol, hydroxyurea, phenytoin.trimethadione, 
retinoids, cadmium, tellurium, triethyltin, glutamate, and 6- 
hydroxydopamine (ILSI 1996). Rats exposed perinatally to 
2,3,7,8-tetrachlorodibenzo-p-dioxin had reduced immune 
function that persisted through puberty and into adulthood 
(Faith and Moore 1977, Gehrs and Smialowicz 1999). A wide 
variety of drugs and toxic chemicals cause birth defects, 
abnormal reproductive development, and infertility in 
experimental animals following exposure during critical periods 
of development. Because sexual differentiation is dependent 
upon hormones and growth factors, a variety of drugs and 
chemicals with androgenic and estrogenic activity as well as 
adrenergic, serotonergic, and opiate activity can alter sexual 
differentiation. Examples of drugs and chemicals that cause 
developmental reproductive effects in experimental animals 
include DES, TCDD, o,p-DDT, methoxychlor, certain fungal 
mycotoxins, tamoxifen, chloredecone, certain PCBs, nitrofen, 
neuroactive drugs, and hexachlorophene (WHO 1986, NRC 
1993, ILSI 1996). 

References: 

Amin-Zaki, L., S.B. Elhassani, M.A. Majeed, T.W. Clarkson, 
R.A. Doherty, and MR. Greenwood. 1980. 
Methylmercury poisoning in mothers and their suckling 
infants. Dev. Toxicol. Environ. Sci. 8:75-78. 

Andersson, U., A.G. Bird, B.S. Britton, and R. Palacios. 1981. 
Humoral and cellular immunity in humans studied at the 
cell level from birth to two years of age. Immunol. Rev. 
57:1-38. 

Barraclough, C.A. 1966. Modification in the CNS regulation of 
reproduction after exposure of prepubertal rats to steroid 
hormones. Recent Progr. Horni. Res. 22:503-539. 
Bellinger, D., A. Leviton, C. Waternaux, H. Needleman, and M. 
Rabinowitz. 1987. Longitudinal analyses of prenatal and 
postnatal lead exposure and early cognitive development. 
N Engl J Med. 316:1037-1043. 


Besunder, J.B., M.D. Reed, and J.S. Blumer. 1988. Principles 
of drug biodisposition in the neonate. A critical evaluation 
of the pharmacokinetic-pharmacodynamic interface (Part 
I). Clin. Pharmacokinet. 14:189-216. 

Braunlich, H. 1981. Excretion of drugs during postnatal 
development. Pharmacol. Then 12:299-320. 

Chakraborti, T., J. Farra, and C. Pope. 1993. Comparative 
neurochemical and neurobehavioral effects of repeated 
chlorpyrifos exposure in young and adult rats. Pharmacol. 
Biochem. Behav. 46:219-224. 

Colten, H R. 1977. Development of host defenses: the 
complement and properdin systems, In: Development of 
Host Defenses, (M.D. Cooperand D.H. Dayton, Eds.), pp. 
165-171. New York, NY: Raven Press. 

Dean, R.F.A. and R.A. McCance. 1947. Inulin, iodine, 
creatinine, and urea clearance in newborn infants. J. 
Physiol. 106:431-439. 

de Mauralt, G. 1978. Maturation of cellular and humoral 
immunity, In: Perinatal Physiology, (W. Stave, Ed.), pp. 
267-315. New York, NY: Plenum Press. 

Dobbing, J. and J. Sands. 1973. Quantitative growth and 
development of human brain. Arch. Dis. Child. 48:757- 
767. 

EPA. (U.S. Environmental Protection Agency). 1992. Demial 
Exposure Assessment: Phnciples and Applications. 
Interim report. Washington, DC: Office of Research and 
Development. 

Faith, R.E and J.A. Moore. 1977. Impairment of thymus- 
dependent immune functions by exposure of the 
developing immune system to 2,3,7,8-tetrac.hlorodibenzo- 
p-dioxin (TCDD). J. Toxicol. Environ. Health 3:451-646. 

Gehrs, B.C. and R.J. Smialowicz 1999. Persistent 
suppression of delayed-type hypersensitivity in adult F344 
rats after perinatal exposure to 2,3,7,8-tetrachlorodibenzo- 
p-dioxin. Toxicology 134:79-88. 

Gershanik, J., B. Boeder, H. Ensley, S. McCloskey and W. 
George. 1982. The gasping syndrome and benzyl 
alcohol poisoning. N. Engl. J. Med.. 307:1384-1388. 

Gilbert, S.G. and K.S. Grant-Webster. 1995. Neurobehavioral 
effects of developmental methylmercury exposure. 
Environ. Health Perspect. 103 (Suppl 6): 135-142. 

Hay, A. 1982. Hexachlorophene. In: The Chemical Scythe 
(E. Hay, Ed.), pp. 69-76. New York, NY: Plenum Press. 

Heise, E.R. 1982. Diseases associated with 
immunosuppression. Environ. Health Perspect. 43:9-19. 

Herbst, A.L., R.J. Kurman, and R.E. Scully. 1972. Vaginal and 
cervical abnormalities after exposure to diethylstilbestrol 
in utero. Obstet. Gynecol. 40:287-298. 

Hill, J.R. 1964. The development of thermal stability in the 
newborn baby. In: The Adaptation of the Newborn to 
Extrauterine Life, pp. 223-228. Netherlands: H.E.Stenfert 
Kroese NV. 

Hoar, R.M. and I.W. Monie. 1981. Comparative development 
of specific organ systems. In: Developmental Toxicology 
(C.A. Kimmel and J. Buelke-Sam, Eds.), pp. 13-33, New 
York, NY: Raven Press. 

Igata, A. 1993. Epidemiological and clinical features of 
Minamata disease. Environ. Res. 63:157-169. 

ILSI. (International Life Sciences Institute). 1996. Research 
Needs on Age-Related Differences in Susceptibility to 


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Chemical Toxicants. Report of an ILSI Risk Science 
Institute Working Group. Washington, DC: ILSI Risk 
Science Institute. 

Jacobson, J. and S. Jacobson. 1996. Intellectual impairment 
in children exposed to polychlorinated biphenyls in utero. 
New Engl. J. Med. 335:783-789. 

Kacew, S. 1992. General principles in pharmacology and 
toxicology applicable to children. In Similarities and 
Differences Between Children and Adults, (P S. Guzelin, 
C.J. Henry and S.S. Olin, Eds.), pp. 24-42. Washington, 
DC: ILSI Press. 

Klinger, W. 1982. Biotransformation of drugs and other 
xenobiotics during postnatal development. Pharmacol. 
Then 16:377-429. 

Kostial, K., D. Kello., S. Jugo, I. Rabar, and T. Maljkovic. 
1978. The influence of age on metal metabolism and 
toxicity. Environ. Health Perspect. 25:81-86. 

Langston, C. 1983. Normal and abnormal structural 
development of the human lung. In: Abnormal Functional 
Development of the Heart, Lungs and Kidneys: 
Approaches to Functional Teratology (R.J. Kavlock and 
C.T. Grabowski, Eds.) pp.75-91. New York, NY: Alan R. 
Liss. 

Libertun, C. and C. Lau. 1972. Adrenocortical function in 
prepubertal rats: neonatal effects on testosterone. J. 
Endocrinol. 55:221-222. 

McLachlan, J.A., R.R. Newbold, K.S. Korach, J.C. Lamb, and 
Y. Suzuki. 1981. Transplacental toxicology: prenatal 
factors influencing postnatal fertility. In: Developmental 
Toxicology. (C.A. Kimmel and J. Buelke-Sam, Eds.) pp. 
213-232. New York, NY: Raven Press. 

Miyawaki, T., N. Moriya, T. Nagaoki, and N. Toniguchi. 1981. 
Maturation of B-cell differentiation ability and T-cell 
regulatory function in infancy and childhood. Immunol 
Rev. 57:61-87. 

Nau, H., W. Luck, and W. Kuhnz. 1984. Decreased serum 
protein binding of diazepam and its metabolite in the 
neonate during the first postnatal week relate to increased 
free fatty levels. Br. J. Clin. Pharmacol. 17:92-98. 

Needleman, H.L. 1995. The role of the environment in injuries 
to the developing nervous system. Environ. Health 
Perspect. 103 (Suppl. 6):77-80. 

NRC. (National Research Council). 1993. Pesticides in the 
Diets of Infants and Children. Washington, DC: National 
Academy Press. 

Owen, J.J.T. 1972. The origins and development of 
lymphocyte populations. In: Ontogeny of Acquired 
Immunity, (R. Porter and J. Knight, Eds.), pp. 35-54, New 


York, NY: Elsevier. 

Peters, H.A. 1976. Hexachlorobenzene poisoning in Turkey. 
Fed. Proc. 35:2400-2403. 

Roder, P.M. 1995. The role of the environment in injuries to 
the developing nervous system.. Environ. Health 
Perspect. 103 (Suppl. 6):73-76. 

Roder, P.M. 1980. Chronology of neuron development: 
animal studies and their clinical implications. Dev. Med. 
Child Neurol. 22:525-545. 

Saenz de Rodriguez, C.A. and M.A. Toro-Sola. 1982. 
Anabolic steroids in meat and premature telarche. Lancet. 
1:1300. 

Schull, W., S. Norton, and R. Jensh. 1990. Ionizing radiation 
and the developing brain. Neurotoxicol. Teratol. 12:249- 
260. 

Sutherland, J.M. 1959. Fatal cardiovascular collapse of infants 
receiving large amounts of chloramphenicol. J. Dis. Child. 
97:761-767. 

Tanner, J.M., R.H. Whitehouse, and M. Takaishi. 1966. 
Standards from birth to maturity for height, weight, height 
velocity, and weight velocity, Part II British children. Arch. 
Dis. Child. 41:613-635. 

Toivanen, P., J. Uksila, A. Leino, O. Lassila, T. Hirvonen, and 
O. Rewskanen. 1981. Development of mitogen 
responding T cells and natural killer cells in the human 
fetus. Immunol. Rev. 57:89-105. 

Tyrala, E.E., L.S. Hillman, R E. Hillman, and W.E. Dodson. 
1977. Clinical pharmacology of hexachlorophene in 
newborn infants. J. Pediatr. 91:481-486. 

Weiss, C.F., A.J. Glazko, and J.K. Weston. 1960. 
Chloramphenicol in the newborn infant: a physiological 
explanation of its toxicity when given in excessive doses. 
N. Engl. J. Med. 252:787-794. ~ 

Wester, R.C. and H.l. Maibach. 1982. Percutaneous 
absorption: neonate compared to the adult. In: 
Environmental Factors in Human Growth and 
Development, Banbury Report No.2, (V.R. Hunt., M.K. 
Smith, and D. Worth, Eds.), pp. 73-84, New York, NY: 
Cold Spring Harbor Laboratory. 

WHO. (World Health Organization). 1986. Principles for 
Evaluating Health Risks from Chemicals During Infancy 
and Early Childhood: The Need for a Special Approach. 
Environmental Health Criteria 59. Geneva, Switzerland: 
World Health Organization. 

Ziegler, E.E., B.B. Edwards, R.L. Jensen, K.R. Mahaffey, and 
S.J. Fomon. 1978. Absorption and retention of lead by 
infants. Pediatr. Res. 12:29-34. 


A-4 



APPENDIX B. ORD RESEARCH PLANS AND STRATEGIES 1 

Name 

Description 

Final Plans and Strategies 

Final Research Plan for Microbial Pathogens 
and Disinfection By-Products in Drinking 
Water (EPA 1997a) 

This research plan was developed to describe research to support EPA’s 
drinking water regulations concerning disinfectants, disinfection by-products, 
and microbial pathogens, focusing on key scientific and technical information 
needed. The research plan was developed by a team of scientists from EPA’s 
national laboratories and centers within the Office of Research and 
Development and from the Office of Water. The plan is intended to provide 
guidance to both the intramural research program and the extramural grants 
program in terms of research priorities and sequencing of research. 

Ecological Research Strategy (EPA 1998a) 

The program goal is to provide the scientific understanding required to 
measure, model, maintain, and/or restore, at multiple scales, the integrity and 
sustainability of ecosystems now and in the future. The research strategy is 
organized around four fundamental research areas: (1) ecosystem monitoring, 
(2) ecological processes and modeling, (3) ecological risk assessment, and (4) 
ecological risk management and restoration. 

Research Plan for Arsenic in Drinking Water 
(EPA 1998b) 

This research plan addresses opportunities to enhance the scientific basis for 
understanding the health risks associated with arsenic in drinking water as well 
as research to support improved control technologies for water treatment. 
Better understanding of arsenic health risks will provide an improved science 
base for arsenic risk assessment and regulatory decisions in the United 
States. Further evaluation of control technologies will support cost-effective 
implementation of future regulatory requirements. 

Strategic Research Plan for Endocrine 
Disruptors (EPA 1998c) 

The plan addresses research needs in the areas of biological effects (both for 
human health and wildlife) and exposure assessment. Importantly, it also 
contains a "linkage" section that strives to integrate effects and exposure 
research to provide a more complete analysis of the risks than has generally 
been done in the past for endocrine disruptors. 

Pollution Prevention Research Strategy 
(EPA 1998d) 

The four long-term goals offered in the research strategy address: (1) tools 
and methodologies for making improved decisions related to pollution 
prevention, (2) technologies and approaches that are preventive or far less 
polluting than those currently in use, (3) verification of the performance of 
pollution prevention alternatives, and (4) economic, social, and behavioral 
issues related to pollution prevention. 

Waste Research Strategy (EPA 1999a) 

The goal of the EPA Office of Research and Development Waste Research 
Strategy is to set forth an effective research program to understand and 
reduce human and ecological exposure to toxic materials released during 
waste management, and to assess and remediate contamination that has 
occurred because of improper waste management. Focus is directed toward 
research on: (1) groundwater at contaminated sites, (2) soils and the vadose 
zone at contaminated sites, (3) active waste management facilities, and (4) 
emissions from waste combustion facilities. Associated technical support 
activities to assist EPA Program Offices, Regions and other stakeholders are 
also described. 

Action Plan for Beaches and Recreational 
Waters (1999b) 

The Beach Action Plan identifies EPA’s multiyear strategy for monitoring 
recreational water quality and communicating public health risks associated 
with potentially pathogen-contaminated recreational rivers, lakes, and ocean 
beaches. 


^his list contains final and draft ORD research plans and strategies as of July 31,2000. Final reports and external review 
drafts can be found on http://www.epa.gov/ORDAA/ebPubs/final/ 


B-1 

















1 APPENDIX B. ORD RESE 

• ' ' ■ - ' . ' ■ • ' , : 

ARCH PLANS AND STRATEGIES (continued) 

Name 

Description 

ORD Strategy for Research on 

Environmental Risks to Children (EPA 

2000). 

The strategy describes the research directions that EPA's Office of Research 
and Development (ORD) will follow in its Children’s Health program. The 
primary objective of the Children’s’s Health program is to conduct research to 
reduce uncertainties in EPA risk assessments for children, leading to effective 
measures to prevent/reduce risk. 

Draft Plans and Strategies 

Mercury Research Strategy (EPA 1999c). 

The strategy presents the goals and scientific questions and associated 
research areas and shapes the agenda for EPA’s mercury research program. 

Airborne Particulate Matter Research 

Strategy (EPA 1999d) 

The strategy describes ORD’s PM research in the areas of health, exposure, 
risk assessment, and risk management. The scope of the strategy 
corresponds to the dual responsibility of EPA to review the adequacy of the 
National Ambient Air Quality Standards (NAAQS) every 5 years and to achieve 
attainment of the NAAQS to protect public health and welfare. The EPA health 
effects and exposure research supports NAAQS review by providing scientific 
methods, models, and data needed for assessment of health risks from PM 
exposures. The EPA research to support implementation of PM standards is 
focused similarly on improving the methods, models, and data for attainment 
decisions. 

Under Development 

Human Health Risk Assessment Research Strategy 

Global Change Research Strategy 

Air Toxics Research Strategy 

Environmental Monitoring and Assessment Program (EMAP) Research Strategy 

Drinking Water Contaminants Candidate List (CCL) Research Plan 

Asthma Research Strategy 


Source: This list contains final and draft ORD research plans and strategies as of July 31,2000. Final reports and external review 
drafts can be found on http://www.epa.gov/ORDAA/ebPubs/final/. 


EPA. (U.S. Environmental Protection Agency). 2000. ORD Strategy for Research on Environmental Risks to Children. 

Washington, DC: Office of Research and Development. EPA/600/R-00/068. 

EPA. 1999a. Waste Research Strategy. Washington, DC: Office of Research and Development. EPA/600/R-98/154. 

EPA. 1999b. EPA Action Plan for Beaches and Recreational Waters. Washington, DC: Office of Research and Development, 
Office of Water. EPA/600/R-78/079. 

EPA. 1999c. Mercury Research Strategy. Workshop review draft. Washington, DC: Office of Research and Development. 
EPA. 1999d. Airborne Particulate Matter Research Strategy. External draft. Research Triangle Park, NC: Office of Research 
and Development. EPA/600/R-99/045. 

EPA. 1998a. Ecological Research Strategy. Washington, DC: Office of Research and Development. EPA/600/R/98-066. 
EPA. 1998b. Research Plan for Arsenic in Drinking Water. Washington, DC: Office of Research and Development. EPA/600/R- 
98/042. 

EPA. 1998c. Strategic Research Plan for Endocrine Disruptors. Washington, DC: Office of Research and Development. 
EPA/600/R-98-087. 

EPA. 1998d. Pollution Prevention Research Strategy. Washington, DC: Office of Research and Development. 

EPA . 1997a. Final Research Plan for Microbial Pathogens and Disinfection By-products in Drinking Water. Washington, DC: 
Office of Research and Development. 


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APPENDIX C. RESEARCH RECOMMENDATIONS 

NRC.(National Research Council). 1993. Pesticides in the Diets of Infants and Children. Washington, DC: National 

Academy Press. 

Differences Between Children and Adults 

■ What are the structural and functional differences between neonates, children of various ages, and adults that can 
potentially influence toxicity of pollutants? 

■ What are the specific periods of development when toxicity can permanently alter the function of a system at maturity? 
What systems continue to mature after birth? 

■ What are the developmental stages of individual biochemical systems, tissues, or organs that enhance, diminish, or alter 
the infant’s or child’s sensitivity to the toxic effects of specific pesticides? 

Selection of Appropriate Animal Models 

■ Compare age-related physiological changes in humans and immature animals of various ages. 

■ Develop appropriate organ-specific functional measures of adverse effect that take into account variable rates of organ 
development within and between species. 


Toxicity 

■ Are mechanisms of action comparable across species and between neonates, infants, children, and adults? 

■ What are the differences in magnitude of response between juvenile test animals and infants/children? 

■ How are neurodevelopmental effects and effects on the immune system in infants and young children measured and 
assessed? 

■ What are the differences in metabolism and deposition in the infant, adolescent, and young adult? 

■ How can physiologic pharmacokinetic modeling be used to forecast how information about metabolism in infant animals 
could be extrapolated to infant humans? 

■ What is the comparison of toxicity in several representative classes of chemicals between adult and immature animals? 

Estimating Exposures 

■ What are the diets and drinking water consumption of infants and children and how do they differ from adult diets? 

■ What are the foods most commonly consumed by young children? 

■ What data are available to develop probability distributions of exposure factors for children? 

■ What are the contributions of exposures from sources other than food and drinking water? 

Estimating Risks 

■ Consider physiological and biological characteristics of infants and children that influence metabolism and disposition and 
develop PBPK models for infants and children. 

■ Develop biologically based models of carcinogenesis for infants and children. 

■ Use benchmark dose for risk assessments for infants and children. 

■ Use risk distributions rather than point estimates.. 

ILSI. (International Life Sciences Institute). 1996. Research Needs on Age-related Differences in Susceptibility to 

Chemical Toxicants. Report of an ILSI Risk Science Institute Working Group. Washington, DC: ILSI Risk Science 

Institute . 

This workshop summarized current knowledge and provided lists of research needs in three areas: cancer, immune 

system effects, and neurotoxicity. 

Cancer 

■ Make better use of existing information on physiological differences between children and adults and information derived 
from common animal models. 

■ Develop appropriate dose metrics for infants and children for given routes and exposure modes. Use PBPK models in 
understanding age-related effects on absorption and distribution in experimental animals and humans. 

■ Develop a comprehensive profile of age-dependent changes in key metabolic enzyme systems of importance in activation 
and deactivation of carcinogens. Perinatal period and time around puberty and adolescence should be high priority. 

■ Perform systematic collection data on changes in cell proliferation rates in various tissues as a function of age in humans 
and relevant experimental animals. 

■ Study age-dependent changes in DNA repair capacity in various tissues from birth through adolescence and for rodent 


C-1 








models in normal populations and populations with heritable DNA defects. 

■ Find biomarkers of carcinogenicity in children as compared with adults. 

■ Conduct more studies of age-dependent effects of nongenotoxic compounds focusing on mechanisms. 

■ Focus in future epidemiology studies on methodologies designed to increase the likelihood of detecting susceptibility 
differences between children and adults. Develop a better understanding of critical time periods for exposure, either for 
certain tumor types or for certain classes of carcinogens. 

■ Examine well-characterized exposures associated with carcinogenesis for age-related differences in the effect. Consider 
feasibility of retrospective studies with data for chemotherapy regimes and appearance of second cancers. 

Immune System Effects 

■ Do chemicals that are known to be immune suppressive or elicit hypersensitivity in adult rodents have similar effects in 
immature animals? (Highest priority). 

■ Assess the responses of children to known protein and/or chemical allergens. 

■ Development of clinical laboratory procedures with sufficient sensitivity to detect changes in measures of immune status. 

■ Wherever possible, identify and characterize genes important in immune ontogeny and immune response. 

Neurotoxicity 

■ Seek consistency with other reproductive /developmental study protocols. 

■ Streamline current tests including neurotoxicity guidelines. 

■ Seek understanding of basic developmental neurobiology and its application in risk assessment. 

■ Develop ability to connect neurobiological function with neurobiological substrates is incomplete: Major categories of 
effects include deficits in cognitive, sensory, autonomic, affective, and motor functions. 

■ Understand the relationship of the neuroendocrine system to the developing nervous system. 


CEHN. (Children’s Environmental Health Network). 1997. 1 st National Research Conferenceon Children’s Environmental 

Health: Research, Pr a ctice, Prevention, Policy. Conference Report. Washington , DC: Children’s Environmental Health 
Network. 

This 3-day conference was organized into six sessions: asthma and respiratory effects, childhood cancer, 
neurodevelopmental effects, endocrine disruptor effects, exposure, and risk prevention and reduction through community 
involvement and education. The recommendations listed below are recommendations of the plenary group. Individual speakers 
also made research recommendations, which are summarized in the conference report. Most of the individual recommendations 
have been captured in the general recommendations. 

General Recommendations 

■ Study developmental processes and identify critical periods of vulnerability. 

■ Study environmental exposures in early life and their relationship to the risk of adult disease and transgenerational effects. 

■ Debate ethical and social issues associated with use of genetic and biomarker information. 

■ Include communities in research agreements that incorporate respect, equity, and empowerment. 

Asthma and Respiratory Disease 

■ Conduct epidemiologic/biologic studies that address the role of environmental exposure to understand why asthma is 
increasing and why incidence is higher in urban minority children. 

• Develop methods to measure air and tissue levels of molds and mycotoxins and investigate their role in pulmonary 

hemorrhage among infants (recommendation of Ruth Etzel in paper on acute pulmonary hemorrhage). 

Endocrine Disruptors 

■ Continued focus on the relationship between endocrine disruptors and cancer, reproductive and developmental 
alterations, and neurological and immunological effects. 

■ Improved understanding of basic endocrine function throughout all stages of human development. 

■ Increase studies of exposure to environmental hormones and their effects at all stages of human development. 

Childhood Cancer 

■ Large biomarker-based case-control studies to evaluate suspect exposures. 

■ Prospective longitudinal studies of children exposed to known or suspected carcinogens, including exposures in utero. 

■ Study cancer susceptibility in children and the interaction between genetic alterations and environmental exposures in 
cancer etiology. 

Neurodevelopmental Effects 

■ Mechanisms of action of toxicants. 


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Health effects of mixtures of neurotoxins, especially pesticides. 

Multigenerational studies of neurotoxicity. 

Techniques to study gene-environment interactions of neurotoxicity. 

Continue studies of neurotoxicity of mercury and PCBs using sensitive outcome measures. 


EPA. (U.S. Environmental Protection Agency). 1998a. U.S. EPA Conference on Preventable Causes of Cancer in 

Children. Conference report. Washington, DC: Office of Children’s Health Protection. 

Four work groups, each chaired by two experts in the work group topic, developed research recommendations. The 

research recommendations appearing below are from the reports of the four work groups as published in EPA (1998c). 

Epidemiology and Prevention 

■ Establish a National Cancer Registry for Childhood Cancers, including information on exposures, especially pesticide 
exposure and dietary intake. 

■ Expand large studies of childhood disease outcomes currently underway. 

■ Develop improved techniques for analyzing clusters by redefining cancer occurring before age 5 as a birth defect. 

■ Examine role of infection/viruses in childhood cancer. 

■ Involve communities, families, and other stakeholders in designing and conducting studies. 

■ Deliver results of research to physicians, nurses, teachers, communities. 

Susceptibility Factors 

■ Investigate differences in carcinogenic metabolism between children and adults, and differences among individuals that 
may predispose some to cancer. 

■ Identify differences in DNA repair that are age-related or genetic. Differential organ development and cancer 
susceptibility. Why are only certain organs the sites of most childhood cancers? Why are there windows of opportunity 
for tumors to form in children? 

■ Determine relationship between diet/obesity in children and cancer development. 

■ Determine whether animal models appropriately reflect exposures and disease. 

■ Increased support to clinical studies supporting prospective registries collecting social, dietary, and exposure factors, and 
stratification of disease subtypes by exposure and molecular marker studies. 

Molecular Markers 

■ Examine more closely the role of environmental exposures that occur preconception, transplacentally, and in the early 
years. 

■ Develop sensitive biomarkers and validate in the laboratory. 

■ Understand mechanisms reflected by biomarkers, their relationship to external exposure, and marker differences between 
children and adults. 

■ Develop noninvasive, painless methods for collecting specimens from children. 

■ Include application of biomarkers in hypothesis-testing studies in conjunction with exposure assessment, personal 
biomonitoring, and validated questionnaires. 

■ Use biomarkers to identify exposed and sensitive populations. 

■ Validate biomarkers for risk assessment. 

Quantitative Measures of Exposure 

■ More closely link exposure data and surrogates/endpoints. 

■ Determine critical metrics researchers should be using (dose, range of dose). 

■ Study children’s activities by age, biology, or function. 

■ Existing data needs to be used as baseline. IRIS-type National Tumor Registry needs to be created as a clearinghouse 
for cancer information. 

■ Conduct exposure studies specifically for children. 


NRDC. (Natural Resources Defense Council). 1997. Our Children at Risk: the 5 Worst Environmental Threats to Their 
Health. San Francisco. CA: Natural Resources Defense Council. 

This document is directed toward legislators and regulators and toward parents, school systems, medical professionals, 
and communities. Most recommendations are for actions that can be taken now to reduce risks. However, it provides a few 
general research recommendations, which are as follows: 

■ Food consumption surveys should include adequate sample sizes of children in the following groups: under 12 months, 
13-24 months, 25-36 months, 37-48 months, 49-60 months, 5-10 years, and 11-18 years. 

■ Measure levels of chemicals in food, air, water, homes, and schools. Identify exposure routes and develop effective 


C-3 









interventions. 

Monitor toxic substances in humans (blood and urine). Develop less costly methods of biomonitoring. 
Identify which toxins have a greater impact on children than on adults. 

Identify critical windows of vulnerability and study developmental processes during periods of vulnerability. 
Improve existing toxicity testing protocols. 


EPA. 1998b. EPA Workshop on the Assessment of Health Effects of Pesticide Exposure in Young Children. Draft report. 

Research Triangle Park, NC: National Health and Environmental Exposure Laboratory. 

Participants were assigned to workgroups corresponding to the disciplines considered relevant for pesticide research 

in children: neurobehavioral disorders, developmental disorders, pulmonary and immune system disorders, and childhood cancer. 

Participants were asked to recommend appropriate endpoints and study designs for human studies. 

Neurobehavioral Work Group 

Endpoints and Tests: 

■ Cognitive skills - Bayley Scales of Infant Development Mental Development Index. 

■ Motor skills - Bayley Scales of Infant Development Psychomotor Development Index. 

■ For older children, a wide range of intelligence, memory, learning, and motor skill tests are available. 

■ Sensory function tests - visual acuity, visual contrast sensitivity, tactile sensitivity. 

Proposed Studies: 

■ Retrospective Acute, High-Exposure Study: Conduct a retrospective cohort study of a fairly small group of children with 
clearly defined, high-level exposure to determine unequivocally whether or not pesticide exposure at acutely toxic levels 
produces neurotoxic effects in young children. The study would address children who had been poisoned by pesticides. 

■ Cross-Sectional Chronic, Low-Exposure Study: If the first study indicates that acute high exposure causes neurotoxic 
effects, further study is warranted. Three chronically-exposed groups - high, medium, and low exposure - would be 
selected based on questionnaire responses with a total of 100 children, age 1.5 to 2.5 years. Purpose is to test whether 
children exposed at lest than acute levels have measurable adverse neurologic effects on psychometric neurologic testing. 

■ Longitudinal cohort study: If chronic low-level exposure is shown to affect neurobehavioral function, administer Bayley 
test and collect urine samples every 3 months starting at 1.5 to 2.5 years. 


Developmental Work Group 

This workgroup decided that in the absence of a clear understanding of the likely pathway and mechanisms by which 
pesticide exposure might influence child development, it would recommend health endpoints for study. Nine endpoints were 
identified. 

Endpoints: 

■ Birth defects, stillborns, spontaneous abortions (priority ranking 1). 

■ Mental, motor, adaptation (priority ranking 1). 

■ Acute poisoning developmental sequelae (priority ranking 1.5). 

■ Growth (priority ranking 1.5). 

■ Language (priority ranking 1.5). 

■ Birth weight, gestational age (priority ranking 2). 

■ Social development (priority rank 4). 

■ Infant mortality, neonatal and postnatal (priority ranking 5). 

■ Puberty, age at menarche, secondary sex characteristics (priority ranking 5). 

■ Hearing (no ranking). 

Proposed Studies: 

■ Prospective prenatal cohort study. 

■ Prospective case-control study of symptomatic children. 

■ Correlation between maternal and infant biologic samples. 

■ Geographic Information System (GIS) studies of infant health status. 


Immunology and Pulmonary Work Group 
Endpoints: 

■ Upper respiratory infections. 

■ Acute bronchitis. 


C-4 





■ Asthma (reactive airway disease). 

■ Interstitial lung disease. 

■ Allergic diseases (allergic rhinitis, eczema, allergic bronchopulmonary aspergillosis). 

■ Immunodeficiency. 

■ Contact dermatitis. 

■ Autoimmune disease. 

■ Inflammatory bowel disease (added because of hypothesis of relation to disorder of immunological system; no known 
association with pesticide exposure). 

■ Infectious disease (associated with immune disorders). 

■ Adverse reproductive endpoints (Hypothesis that immunopathology in adult female may contribute to adverse reproductive 
outcomes). 

Proposed Studies: 

■ Pilot study of immunologic status and development of infants exposed to pesticides. 

■ Longitudinal study of a birth cohort. 

■ Survey of border families. 

■ Case-control study of children exposed to pesticides. 

■ Case-control study of children with hyper reactive airways. 


Cancer 

This work group focused on childhood cancer and considered several possible types of studies: (1) using existing 
databases, (2) performing an ecological study that would geographically compare pesticide usage and cancer incidence, (3) 
performing a case-control study that would identify cases and then determine if the cancers were associated with pesticide cancer, 
(4) conducting a prospective cohort study that might link exposure to a biomarker and then to cancer, (5) conducting a study that 
could link cancer-relevant biomarkers with pesticide exposure. 

The work group’s conclusion was as follows: 

"....In all cases, the questions associated with the exposure assessment compromised the conclusions that might 
be done from the study....The workgroup...concluded and strongly recommended that the issues associated with 
proper exposure information be solved prior to conducting an analysis of the health outcome.... 

“....the group strongly recommended that resources be focused first on improving the approaches to exposure 
assessment. Also, other efforts are already underway investigating childhood cancers, developing databases, and 
evaluating approaches to using biological markers... .Once the exposure assessment can be more adequately conducted, 
and the information about the cancer studies is available, it should be possible to revisit and make recommendations 
concerning studies to investigate the association of childhood cancers and exposures to pesticides.” 


C-5 





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APPENDIX D. FEDERAL RESEARCH ON CHILDREN’S 

ENVIRONMENTAL HEALTH 

Agency 

Examples of Collaborations with 

EPA on Children’s Health Research 

Other Major Programs of Interest 

Department of Health and Human 
Services (DHHS) National Institutes 
of Health - conducts research in its own 
laboratories; supports the research of 
scientists in universities, medical 
schools, hospitals, and research 
institutions throughout the U.S. and 
abroad; helps in the training of research 
investigators; and fosters 
communication of medical information. 

All Institutes of Health that are members 
of the U.S. Task Force on Children’s 
Environmental Health and Safety are 
participating in an investigation of the 
feasibility of a federally sponsored 
longitudinal birth cohort study. 

See the components of DHHS. 

DHHS/NIH, National Cancer Institute - 

sponsors and conducts research on 
prevention, detection, and treatment of 
cancer, including research on biological, 
genetic, and environmental causes of 
cancer and clinical trials of treatments. 

Agricultural Health Study - The goal is to 
establish a large prospective cohort of 
agricultural workers, their spouses, and 
dependents, that can be followed for 10 
or more years, to evaluate the role of 
agricultural and related exposures in the 
development of cancer, neurologic 
diseases, reproductive and 

developmental outcomes, and other 
chronic diseases. 

Clinical trials of treatment methods for 
childhood cancer (Children's Cancer 
Group, Pediatric Oncology Group, 
National Wilms' Tumor Study Group, 
and Intergroup Rhabdomyosarcoma 
Study Group) 

DHHS/NIH, National Institute of 
Allergy and Infectious Diseases - 
provides the major support for scientists 
conducting research aimed at 
developing better ways to diagnose, 
treat, and prevent the many infectious, 
immunologic, and allergic diseases that 
afflict people worldwide. 

Inner-City Asthma Study - This study 
examines respiratory symptoms and 
pulmonary function levels in children with 
moderate to severe asthma in seven 
communities. EPA is sponsoring 

monitoring of indoor and outdoor 
particulate matter and co-pollutants. 

Genetic Susceptibility and Variability of 
Human Malformations (STAR program 
with NICHD, NIDCR, and NIEHS) - This 
study examines relationships between 
genetic polymorphisms, gene- 
environment interactions, and birth 
defects. 


DHHS/NIH, National Institute of Child 
Health and Human Development - 

conducts and supports laboratory, 
clinical, and epidemiological research 
on the reproductive, neurobiologic, 
developmental, and behavioral 
processes that determine and maintain 
the health of children, adults, families, 
and populations. 

Genetic Susceptibility and Variability of 
Human Malformations (ORD STAR 
program with NICHD, NIDCR, and 
NIEHS). 


DHHS/NIH, National Institute of 
Dental and Craniofacial Research - 

improves oral, dental and craniofacial 
health though science and science 
transfer. 

Genetic Susceptibility and Variability of 
Human Malformations (ORD STAR 
program with NICHD, NIDCR, and 
NIEHS) 



D-1 



















APPENDIX D. FEDERAL RESEARCH ON CHILDREN’S 
ENVIRONMENTAL HEALTH (continued) 


Agency 


Examples of Collaborations with 
EPA on Children’s Health Research 


Other Major Programs of Interest 


DHHS/NIH National Institute of 
Environmental Health Sciences - 

investigates the role and interaction of 
environmental factors, individual 
susceptibility, and age in human illness 
and dysfunction through 
multidisciplinary biomedical research 
programs, prevention and intervention 
efforts, and communication strategies. 


Genetic Susceptibility and Variability of 
Human Malformations (ORD STAR 
program with NICHD, NIDCR, and 
NIEHS). 

Cosponsor of 8 Centers for Children’s 
Environmental Health and Disease 
Prevention Research. (ORD STAR 
program). 


Environmental Genome Project - 
identification and establishment of a 
database of polymorphisms of 
environmental disease susceptibility 
genes. 


Agricultural Health Study (with NCI and 
NIEHS). 


DHHS, Centers for Disease Control 
and Prevention - conducts medical 
surveillance, reports public health 
statistics, seeks causes for public health 
emergencies, and conducts research. 


Study exposure to pesticides and 
potential adverse effects in children 
living along the U.S.-Mexico border. 

NHANES IV study of children’s exposure 
to pesticides and adolescents’ exposure 
to persistent, bioaccumulative toxins. 


Surveillance of childhood asthma and 
birth defects. 

NHANES IV - collection of data on 
health and nutrition in the U.S. 
population, including several thousand 
children and adolescents. 


NHANES study of lead exposures in 
children (with HUD). 


DHHS, Agency for Toxic Substances 
and Disease Registry - advises EPA 
and others on public health impacts of 
hazardous waste sites, determines 
levels of public health hazard, conducts 
health studies in communities near 
sites, and supports research. 


ATSDR conducts evaluations of the 
health of children and adults near 
Superfund sites and other hazardous 
waste sites. ATSDR makes 
recommendations to EPA on public 
health issues. 


Department of Housing and Urban 
Development - protects children in 
the home through regulations dealing 
with hazards such as lead-based paint 
and supports research on exposures 
and remedial actions. 


NHANES study of lead exposures in 
children (with CDC). 


D-2 
















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*U.S. GOVERfMEKT PRIOTTNG OFFICE: 2000-651-093/40904 














































































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0 007 231 041 A 


EPA/600/R-00/068 



























































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